Antioxidants 10 00186 Published

antioxidants
Review
Redox Homeostasis in Poultry: Regulatory Roles of NF-κB
Peter F. Surai 1,2,3,4,5, * , Ivan I. Kochish 2 and Michael T. Kidd 6
1 Department of Biochemistry, Vitagene and Health Research Centre, Bristol BS4 2RS, UK
2 Department of Hygiene and Poultry Sciences, Moscow State Academy of Veterinary Medicine and
Biotechnology named after K. I. Skryabin, 109472 Moscow, Russia; [email protected]
3 Department of Biochemistry and Physiology, Saint-Petersburg State Academy of Veterinary Medicine,
196084 St. Petersburg, Russia
4 Department of Microbiology and Biochemistry, Faculty of Veterinary Medicine, Trakia University,
6000 Stara Zagora, Bulgaria
5 Department of Animal Nutrition, Faculty of Agricultural and Environmental Sciences, Szent Istvan
University, H-2103 Gödöllo, Hungary
6 Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA;
[email protected]
* Correspondence: [email protected]
Abstract: Redox biology is a very quickly developing area of modern biological sciences, and roles of
redox homeostasis in health and disease have recently received tremendous attention. There are a
range of redox pairs in the cells/tissues responsible for redox homeostasis maintenance/regulation. In
general, all redox elements are interconnected and regulated by various means, including antioxidant
and vitagene networks. The redox status is responsible for maintenance of cell signaling and cell
stress adaptation. Physiological roles of redox homeostasis maintenance in avian species, including
poultry, have received limited attention and are poorly characterized. However, for the last 5 years,
this topic attracted much attention, and a range of publications covered some related aspects. In fact,
transcription factor Nrf2 was shown to be a master regulator of antioxidant defenses via activation of

various vitagenes and other protective molecules to maintain redox homeostasis in cells/tissues. It
was shown that Nrf2 is closely related to another transcription factor, namely, NF-κB, responsible for
Citation: Surai, P.F.; Kochish, I.I.;
Kidd, M.T. Redox Homeostasis in
control of inflammation; however, its roles in poultry have not yet been characterized. Therefore,
Poultry: Regulatory Roles of NF-κB. the aim of this review is to describe a current view on NF-κB functioning in poultry with a specific
Antioxidants 2021, 10, 186. https:// emphasis to its nutritional modulation under various stress conditions. In particular, on the one
doi.org/10.3390/antiox10020186 hand, it has been shown that, in many stress conditions in poultry, NF-κB activation can lead to
increased synthesis of proinflammatory cytokines leading to systemic inflammation. On the other
Academic Editor: Evangelos Zoidis hand, there are a range of nutrients/supplements that can downregulate NF-κB and decrease the
Received: 14 December 2020 negative consequences of stress-related disturbances in redox homeostasis. In general, vitagene–
Accepted: 25 January 2021 NF-κB interactions in relation to redox balance homeostasis, immunity, and gut health in poultry
Published: 28 January 2021
production await further research.
Publisher’s Note: MDPI stays neutral Keywords: antioxidants; NF-κB; oxidative stress; poultry; redox balance
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
1. Introduction
Redox biology is a very quickly developing area of modern biological sciences, and
roles of redox homeostasis in health and disease have recently received tremendous at-
Copyright: © 2021 by the authors.
tention [1–6]. There are a range of redox pairs in cells/tissues responsible for redox
Licensee MDPI, Basel, Switzerland.
homeostasis maintenance/regulation. They include, but are not limited to, NAD+ /NADH,
This article is an open access article
NADP+ /NADPH, GSSH/GSH (glutathione system), Trxox /Trxred (thioredoxin system),
distributed under the terms and
conditions of the Creative Commons
protein thiolsox /protein thiolsred . It is believed that redox signaling is tightly integrated
Attribution (CC BY) license (https://
with various homeostatic mechanisms [7] and all redox elements are interconnected and
creativecommons.org/licenses/by/ regulated by various means, including antioxidant and vitagene networks [1]. The redox
4.0/). status is responsible for maintenance of cell signaling and cell stress adaptation. There are
Antioxidants 2021, 10, 186. https://doi.org/10.3390/antiox10020186 https://www.mdpi.com/journal/antioxidants

Antioxidants 2021, 10, 186 2 of 50
a range of redox sensors which determine redox imbalance and activate various pathways
for its re-establishment. Among them are proteins Keap1, an inhibitor of Nrf2, and IκB,
an inhibitor of NF-κB, which have received a lot of recent attention. Indeed, oxidation of
SH groups in Cys of Keap1 or phosphorylation of IκB are important triggers for nuclear
translocation and activation of Nrf2 and NF-κB—important players in the redox home-
ostasis regulation [6]. In particular, a recent model suggests regulation of all collaborating
metabolic organs in the body through changes in circulating redox metabolites [5].
The physiological roles of redox homeostasis maintenance in avian species, including
poultry, are poorly characterized. However, for the last 5 years, this topic attracted a lot
of attention, and a range of publications covered some related aspects. Indeed, the redox
system imbalance is shown to be associated with protein oxidation and impaired quality
of poultry meat [8,9]. In broilers, subjected to dietary and heat stress, magnesium sup-
plementation was indicated to improve redox status and meat quality [10]. The influence
of selenium and selenoproteins in maintaining redox balance and immune responses of
poultry and pigs was presented [11], and the effect of oxidative stress and redox disbalance
on inflammation, including a detailed immune system investigation, was discussed [12,13].
Oxidative stress-related disturbances of the redox balance in the poultry gut have also
been described [13–16]. The long-term effects of Ochratoxin A on the glutathione redox
system in chickens have been investigated [17], and the protective effects of milk thistle on
redox-homeostasis imbalance of duck liver imposed by mycotoxins [18] were shown. Fur-
thermore, the detrimental effects of heavy metals (e.g., As) on redox imbalance in chickens
have been reported [19]. Nutritional modulation of the antioxidant capacities and redox
homeostasis in poultry by selenium [13,20], vitamin E [21], and carotenoids [22], including
astaxanthin [23], has been described. Recently, the vitagene concept of stress adaptation
was developed, and questions related to redox balance maintenance in poultry under vari-
ous stress conditions were addressed [1]. In fact, the vitagene family includes superoxide
dismutase (SOD), heat shock protein 70 (HSP70), heme oxygenase 1(HO-1), elements of
thioredoxin and glutathione systems, and sirtuins [24–26]. Indeed, induction/activation of
the aforementioned genes leading to synthesis/expression of protective molecules helps
animals/poultry adapt to stress by using their internal resources to the maximum extent.
Furthermore, transcription factor Nrf2 was shown to be a master regulator of an-
tioxidant defenses via activation of various vitagenes and other protective molecules to
maintain redox homeostasis in cells/tissues [1,27]. It was shown that Nrf2 is closely related
to another transcription factor, namely, NF-κB, responsible for control of inflammation;
however, its roles in poultry are not yet characterized. The importance of understanding
the molecular mechanisms of redox homeostasis maintenance and the regulatory roles of
NF-κB in this process is related to several important issues in poultry production. Firstly,
intensive poultry production is related to a variety of stresses which cannot be avoided
because of price-sensitive production of meat and eggs [28–30]. Secondly, commercial
poultry production is based mainly on large production units where several hundred birds
are kept in a single room. In such conditions, immune protection against various micro-
bial and viral diseases becomes an important issue, and several vaccinations during the
production period take place [31]. Therefore, the important roles of NF-κB in maintaining
the high immunocompetence of commercial birds deserve more attention. Because of
growth-promoting antibiotic prohibition in poultry production in many countries with
developed poultry production, poultry farmers face a lot of challenges associated with gut
health problems and immunosuppression [32,33], where NF-κB is known to be involved.
The global poultry industry faces challenges from Salmonella contamination of meat and
eggs [34–36] and Campylobacter contamination of chicken meat [37], and understanding
NF-κB functioning in poultry may help to develop effective protective measures against
the aforementioned pathogens. Avian flu is also a great challenge for the global poultry
industry [38], and understanding the involvement of NF-κB in antiviral immunity is on the
agenda of many research centers worldwide. Furthermore, the avian immune system has a
range of differences from the mammalian immune system (e.g., absence of lymph nodes,
different antibody repertoire, absence of myeloperoxidase in macrophages, etc.) [39–41]

and, therefore, understanding the regulatory functions of NF-κB would help to design
various approaches for immunomodulation [42]. Lastly, there are a range of inflammation-
associated conditions in poultry (see Section 8) where the crucial role of NF-κB is well
known [43,44].
Therefore, the aim of this review is to provide and describe a current view on the
NF-κB system functioning in poultry as an important part of redox balance maintenance
mechanisms with a specific emphasis on the nutritional modulation of NF-κB under
various stress conditions. For this purpose, a literature search using key words “NF-κB”
and “poultry” or “chicken” was conducted using PubMed and Web of Science. Results
of the analysis of relevant papers were included into the review. Since we were not able
to find any reviews related to the roles of NF-κB in poultry, published in peer-reviewed
journals, we also provide general information about the structure and functions of NF-κB
on the basis of recent publications in this area.
2. Transcription Factor Nuclear Factor Kappa B

Nuclear factor kappa B (NF-κB) was discovered in the lab of the Nobel Prize winner,
David Baltimore, as an inducible transcription factor in lymphocytes [45]. In general,
NF-κB structure, functions, and regulation have been extensively characterized in recent
comprehensive reviews [46–48]; however, in this review, the major emphasis is given
to oxidative stress and the roles of NF-κB in the regulation of adaptive homeostasis in
avian species.
The NF-κB family consists of several transcription factors characterized by Rel-
homology domains (RHDs) that are able to bind to specific DNA sequences known as κB
sites located in the promoter and enhancer regions of various genes [49]. It has been found
that NF-κB is conserved across different phyla, and, in mammalian and avian species, it
consists of a group of five related proteins (subunits) that are capable of binding to DNA:
p50 (a 50 kDa protein also known as NF-κB1), p52 (known as NF-κB2), p65 (also known
as RelA), c-Rel, and RelB. In fact, p65, RelB, and c-Rel are characterized by a C-terminal
transcription activation domain (TAD) that participates in the positive regulation of gene
expression [50]. Interestingly, the other NF-κB family members, NF-κB1 and NF-κB2, were
shown to be synthetized as larger precursor proteins (p105 and p100) with subsequent
proteolytic processing to p50 and p52 [47]. Transcription factor subunits of NF-κB, for
example, p65, can combine to form hetero- and homodimers of different composition,
defined as the NF-κB complex. As a result of binding to a variety of DNA sequences called
κB sites, NF-κB can effectively regulate different gene targets [51].
By using two independent LC–MS/MS experiments, 365 NF-κB/RelA-associated
proteins were identified [52]. The functional categories enriched in the newly identified
NF-κB/RelA-associated proteins identified by the authors include DNA-binding factors
and enzymes, RNA-binding factors and enzymes, nuclear matrix and cytoskeleton com-
ponents, ribosome biogenesis, protein degradation, and mitochondrial proteins. For the
maintenance of redox balance and development of adaptive homeostasis, the last category
related to mitochondrial proteins, including antioxidant proteins, namely, peroxiredoxins
3 and 1 (PRDX3, and PRDX1), is of great importance. Functional analysis of the newly
identified RelA-binding proteins conducted by the authors confirmed the complexity of
the NF-κB actions and its involvement in the regulation of important biological functions
including regulation of protein ubiquitination, chromatin organization, response to DNA
damage stimulus, post-transcriptional regulation of gene expression, cell-cycle progress,
and microtubule cytoskeleton translation [52]. Interestingly, an update on NF-κB and
proteomics published a year earlier [53] indicated that stimulation of specific receptors by
RNA, DNA, or lipopolysaccharide (LPS) is associated with the interactions of a number of
unique proteins regulating NF-κB expression and activity, which activate a range of genes
creating an adaptive response. Indeed, their roles in the maintenance of redox balance and
the creation of adaptive homeostasis via modulating transcription factors and vitagenes
deserve more attention.
Dimerization takes place at a region named the RHD, which is essential for DNA
binding, dimerization, and interaction with the inhibitory κB (IκB) proteins [54,55]. The
p65/50 dimer is considered to be the most important dimer activating transcription. Hence,
RelA-deficient mice are shown to be embryonically lethal as a result of liver apoptosis [56].
As a result of action by various stimuli, IκB proteins are known to be rapidly phos-
phorylated by IκB kinase (IKK) on specific serine residues (e.g., Ser-32 and Ser-36 of IκBα;
Ser-19 and Ser-23 of IκBβ), followed by ubiquitination (by E2- and E3-ligases), and degra-
dation by the 26S proteasome [57]. To make signaling more effective, on the one hand,
NF-κB is shown to encode gene effectors potentiating and amplifying its activation in a
feedforward fashion. On the other hand, NF-κB activation is associated with program-
ming default feedback mechanisms responsible for its automatic termination (post mission
completion) by regulating the amount/activity/expression of negative effectors including
microRNAs (miRNAs), decoy receptors, and anti-inflammatory cytokines, which can lead
to the inhibition of the signaling pathways, inhibitory proteins IκBα and IκBε, etc. [58–60].
There are some similarities in the regulation of Nrf2 and NF-κB in biological systems.
For example, in physiological resting conditions, NF-κB is known to be located in the
cytoplasm of cells in an inactive state tightly bound to the inhibitory IκB proteins (e.g.,
IκBα, IκBβ, IκBγ, IκBδ, IκBε, etc.) preventing its binding to target sites. It seems likely
that the IκB proteins are responsible for masking the DNA-binding domain of NF-κB/REL
proteins, leading to their sequestering in the cytoplasm. Interestingly, IκB proteins are
responsible for checking and controlling the pathway due to nuclear export signals and
their ability to remove NF-κB proteins from the nucleus [59].
It seems likely that key steps in the NF-κB pathway include activation by the IκB
kinase (IKK) complex, leading to the phosphorylation-induced proteasomal degradation
of IκB proteins, dimer formation, and entering the nucleus, with subsequent binding to
κB sites in promotor or enhancer regions of target genes [61]; along with other cofactors
and histone acetyl transferases [62], it is also responsible for the transcription of more
than 400 target genes regulating inflammation, immunity, apoptosis, stress adaptation, cell
proliferation, and differentiation [63,64]. Major classes of target genes for NF-κB are shown
in Figure 1.
As can be seen from the data presented in Figure 1, NF-κB target genes can be divided
into several groups. The main group includes genes directly related to immunity, including
immunoreceptors, proteins involved in antigen presentation, cytokines/chemokines and
their modulators, and acute phase proteins. The second group of genes regulated by
NF-κB are associated with stress adaptation and homeostasis maintenance under various
stress conditions, including transcription factors and regulators, stress response genes,
and early response genes. The third group of NF-κB-regulated genes are responsible for
the regulation of various cellular function, including regulators of apoptosis, cell-surface
receptors, cell adhesion molecules, growth factors, and their modulators. There are also
NF-κB-regulated genes related to viruses, enzymes, and some other important signaling
molecules. Therefore, the great variety of NF-κB-regulated genes explains the pivotal roles
of this transcription factor in major physiological and pathophysiological processes in
mammalian and avian species.
Generally, the NF-κB system is tightly regulated and can be activated by more than
15 pathways, with the two most common pathways being canonical (classical) and non-
canonical (alternative) pathways [57]. The canonical pathway (i.e., the classical pathway) is
based primarily on usage of p50 (the product of p105) in conjunction with p65 (p65/p50
nuclear dimer), IKKβ, and NF-κB Essential Modulator (NEMO), and it can be activated
by pro-inflammatory cytokine receptors (interleukin 1 receptor, IL-1R and tumor necrosis
factor receptor, TNFR), by pattern recognition receptors including the Toll-like receptors
(TLRs), and by various genotoxic agents. It seems likely that the NF-κB stimulation by
various external and internal stressors takes place via the canonical pathway. This in-
cludes a response to genotoxic and oxidative stresses, caused by ultraviolet radiation,

ionizing radiation, reactive oxygen species (ROS), hypoxia, and dysfunctional mitochon-
dria or endoplasmic reticulum by activating NF-κB IKK-dependently, IKK-independently,
Antioxidants 2021, 10, x FOR PEER REVIEW 5 of 50
or both [60,66,67]. In particular, NF-κB can be activated by DNA damage via the canonical
pathway [68].
Figure 1. NF-κB target genes (adapted from [65]).
Thecan
As noncanonical
be seen frompathway (known asinthe
the data presented alternative
Figure 1, NF-κB pathway) is associated
target genes with
can be divided
p52 (the product of p100), RelB, NF-κB-inducing kinase (NIK), and IKKα
into several groups. The main group includes genes directly related to immunity, includ- and it is known
to beimmunoreceptors,
ing triggered by a range of stimuli,
proteins including
involved lymphotoxin
in antigen B receptor,
presentation, B-cell activating
cytokines/chemokines
factor receptor 3, cluster of differentiation 40 (CD40), and receptor
and their modulators, and acute phase proteins. The second group of genes regulated activator of NF-κBby
ligand are
NF-κB (RANKL).
associatedTherefore,
with stressligand-induced
adaptation and activation
homeostasisof themaintenance
aforementioned under receptors
various
leads to
stress the activation
conditions, of NF-κB-inducing
including transcription kinase
factors(NIK), which specifically
and regulators, activatesgenes,
stress response IKK1,
inducing the phosphorylation and proteolytic processing of p100
and early response genes. The third group of NF-κB-regulated genes are responsible for to p52, followed by
heterodimer formation with RelB to regulate target gene expression [56].
the regulation of various cellular function, including regulators of apoptosis, cell-surface It is established
that the noncanonical
receptors, cell adhesionNF-κB pathway
molecules, is deeply
growth factors,involved
and their inmodulators.
regulation ofThere
the immune
are also
NF-κB-regulated genes related to viruses, enzymes, and some other importantregulation
system, including creation of the adaptive immune response [69]. This includes signaling
of B-cell development and function, including differentiation into long-lived antibody-
molecules. Therefore, the great variety of NF-κB-regulated genes explains the pivotal roles
producing plasma cells and memory B cells (for a review, see [46,70]), both being an
of this transcription factor in major physiological and pathophysiological processes in
integral part of the humoral immune response. Since, in comparison to mammals, avian
mammalian and avian species.
spices are characterized by a different set of immunoglobulin (Ig) classes (IgD and IgE
Generally, the NF-κB system is tightly regulated and can be activated by more than
molecules are absent in birds) and a different cytokine repertoire [41], understanding the
15 pathways, with the two most common pathways being canonical (classical) and non-
molecular mechanisms underlying regulation of the noncanonical NF-κB pathway in birds
canonical (alternative) pathways [57]. The canonical pathway (i.e., the classical pathway)
is a priority for avian scientists. Furthermore, a range of vaccinations used in poultry
is based primarily on usage of p50 (the product of p105) in conjunction with p65 (p65/p50
production are based on humoral response activation and memory B-cell formation [31,71],
nuclear dimer), IKKβ, and NF-κB Essential Modulator (NEMO), and it can be activated by
and the noncanonical NF-κB pathway could be a target for improvement of vaccination
pro-inflammatory cytokine receptors (interleukin 1 receptor, IL-1R and tumor necrosis
efficacy. It should be mentioned that the noncanonical NF-κB pathway was also shown
factor receptor,TNFR), by pattern recognition receptors including the Toll-like receptors
to be involved in T-cell development in the thymus, and in orchestrating the formation
(TLRs), and by various
and maintenance genotoxic
of effector agents.TItcells
and memory seems[65].likely thatthe
Indeed, thecell-mediated
NF-κB stimulation
immunity by
various external and internal stressors takes place via the canonical pathway. This in-
cludes a response to genotoxic and oxidative stresses, caused by ultraviolet radiation, ion-
izing radiation, reactive oxygen species (ROS), hypoxia, and dysfunctional mitochondria
or endoplasmic reticulum by activating NF-κB IKK-dependently, IKK-independently, or
both [60,66,67]. In particular, NF-κB can be activated by DNA damage via the canonical
based on T-cell activity is of paramount importance for poultry, including resistance to

viral diseases and vaccination efficacy [72,73].
It is important to mention that canonical and noncanonical NF-κB pathways interact
with each other. For example, in the classical NF-κB pathway, the first protein transcribed
is IκBα. Therefore, it is believed that, in order to inhibit further transcription and restore
the original latent state of NF-κB signaling, newly synthesized IκBα can enter the nucleus,
remove NF-κB from DNA, and export the complex back to the cytoplasm [49]. Interestingly,
the canonical NF-κB pathway is considered to be antiapoptotic, while the noncanonical
pathway is proapoptotic [50].
It well known that NF-κB responds to a large variety of external and internal stress sig-
nals/stimuli including oxidative stress [62], playing essential roles in the development and
maintenance of tissue homeostasis by regulating the transcription of an array of different
genes, including proinflammatory cytokines, as well as adhesion molecules, antimicrobial
peptides, and acute phase proteins [74–76]. In fact, NF-κB signaling can be considered as
an emergency response system, since activation of NF-κB was shown to occur very quickly
(within minutes) as a result of release from IκB or as a consequence of cleavage of the in-
hibitory ankyrin repeat domains of p100 and p105 [50]. Under physiological conditions, the
majority of NF-κB-activated genes regulate biological processes associated with cell growth,
protection, and repair. They are involved in T-cell maturation, DNA damage repair, tissue
healing after injury, and orchestrating the fight against infections [60,67]. Indeed, it has
been proven that activation of NF-κB is an evolutionarily conserved, effective mechanism
of host defense against infection and stress [77]. However, excessive NF-κB activation in
commercially relevant stress conditions in poultry and farm animal production systems can
lead to detrimental consequences, including chronic inflammation, compromised health
status, and decreased productive and reproductive performance. The repertoire of stimuli
implicated in the NF-κB activation is very diverse and also includes inhibitory κB kinases,
cell-surface receptors, and NF-κB-inducible inhibitor proteins (IB proteins), as well as
factors regulating the post-translational modification of the Rel proteins, etc. [63,64,74–76].
Furthermore, p65 and p50 are the targets of many other post-translational modifications
such as ubiquitination, acetylation, methylation, phosphorylation, oxidation/reduction,
and prolyl-isomerization, leading to a change in NF-κB transcriptional activity due to af-
fecting the interaction with DNA or as a result of changes in the protein–protein association
of NF-κB [78].
NF-κB signaling in numerous cell types is involved in the development of various
metabolic disorders. In particular, it is thought that resident tissue cells activate NF-
κB in response to stress associated with nutrient excesses [58]. Furthermore, oxidized
lipids in the bloodstream can induce NF-κB in vascular endothelia, while, in adipocytes,
hepatocytes, and neurons, NF-κB is induced by metabolic or oxidative stress in the ER due
to overnutrition. Furthermore, an excess of free fatty acids could also activate NF-κB via
TLR4 [58]. Some examples of activation of NF-κB associated with regulation of downstream
transcriptional antioxidant and pro-oxidant targets in the canonical pathway are shown in
Figure 2.
Depending on physiological context, the activation of NF-κB can have different conse-
quences. Indeed, NF-κB does not function alone but is part of various networks, including
crosstalk with other transcription factors (Nrf2; signal transducer and activator of transcrip-
tion 3, STAT3; Forkhead box O3, FOXO3; etc.), upstream kinases, sirtuins, Wingless-related
MMTV integration site 4 (Wnt4), ROS, p53, and miRNAS, which determine the pattern of
its effects on the expression of a battery of various genes [48,60,67]. Furthermore, there
are regulatory mechanisms coordinating NF-κB association with various important path-
ways [50]. It has been suggested to consider NF-κB as a stress response factor, since NF-κB
signaling is condition-dependent, and NF-κB-dependent cell death or survival would
depend on the stimulus and the cell type involved. It seems likely that this complexity is
responsible for many apparent contradictions in the literature [79]. However, most research
related MMTV integration site 4 (Wnt4), ROS, p53, and miRNAS, which determine the
pattern of its effects on the expression of a battery of various genes [48,60,67]. Further-
more, there are regulatory mechanisms coordinating NF-κB association with various im-
portant pathways [50]. It has been suggested to consider NF-κB as a stress response factor,
since NF-κB signaling is condition-dependent, and NF-κB-dependent cell death or sur-
vival would depend on the stimulus and the cell type involved. It seems likely that this
complexity is responsible for many apparent contradictions in the literature [79]. How-
ever, most research data indicate that NF-κB signaling pathway enables cells to maintain
homeostasis
data indicateand
that survive under various
NF-κB signaling stress
pathway conditions,
enables cells to including genotoxic stress
maintain homeostasis and
[60,67].
survive under various stress conditions, including genotoxic stress [60,67].
Activation of NF-κB and regulation of downstream transcriptional antioxidant

Figure 2. Activation antioxidant and pro-oxidant
pro-oxidant targets in the
canonical pathway (adapted from [1,59,80–84]).
NF-κB is involved in the modulation of many different molecular events, including

inflammation, immune function, cellular growth, and apoptosis [46,70]. There are a range of
NF-κB activators, including pathogen-derived substances (LPS) and inflammatory signals
(TNF-α, IL-1), as well as other signals recognized by various receptors, including TNFRs,
TLRs, T-cell receptors (TCRs), B-cell receptors (BCRs), and cytokine receptors, which lead
to an activation of IκB kinase (IKK) with subsequent phosphorylation of NF-κB inhibitor.
This leads to proteasomal degradation of IκB. As a result, the released NF-κB migrates into
the nucleus and binds with its corresponding DNA-responsive elements in the presence
of coactivators. This results in the transcription of antioxidant (anti-inflammatory) or
pro-oxidant (proinflammatory) mediators [46,85]. It is believed that p65 can induce the
expression of both negative regulators (IκBα, IκBε, etc.) and positive regulators (Relα,
TNFα, etc.) participating in tuning the NF-κB pathway [83]. It is important to mention
that NF-κB can be directly activated or inhibited by ROS in a context-dependent manner,
including levels of ROS, exposure, and cell type [59,86,87]. Indeed, ROS-mediated oxidation
of redox-sensitive cysteine residues of NF-κB subunits was shown to have dual effects
(inducing or inhibiting) on the NF-κB signaling depending on the level of ROS, the cell type,
and the types of stimuli [81,88]. On the one hand, ROS can activate the NF-κB pathway by
imposing disulfide bond formation between Cys54 and Cys347 in IKKγ [89]. On the other
hand, ROS can have an opposite effect: inhibiting NF-κB activation as a result of restricting
IκBα degradation, due to inactivation of the proteasome [90].
The NF-κB system integrates diverse upstream input signals (from various stresses
to pathogen-related molecules) recognized by various receptors into varied downstream
output responses. This function is mediated via promotion of the expression of a variety
of genes responsible for the synthesis of antioxidant or prooxidant molecules, improving

antioxidant defenses and redox homeostasis. Alternatively, NF-κB activation can also
lead to synthesis of proinflammatory cytokines, imposing inflammation and causing
detrimental health- and production-related consequences in poultry and farm animals. In
particular, NF-κB and STAT3 regulate common processes and share regulatory binding
sites of antiapoptotic, cell cycle and proliferation, tissue resistance, and repair genes.
Furthermore, hypoxia-inducible factor (HIF) and NF-κB share common activating stimuli,
regulators, and targets [61].
3. NF-κB and Oxidative Stress

Free-radical production is considered to be an important process in biological systems
responsible for the antibacterial action of oxidative burst in phagocytes, cell signaling,
and stress adaptation [7]. However, an excess of reactive oxygen and nitrogen species
(RONS) due to high level of stress or a compromised antioxidant system leads to damages
to major biological molecules (proteins, polyunsaturated fatty acids (PUFAs), DNA, etc.)
associated with immunosuppression, gut health problems, and decreased productive and
reproductive performance of poultry [30]. Therefore, a variety of protective mechanisms
have been developed during evolution to deal with RONS excess, and many transcription
factors are involved in this process via regulating vitagenes and a myriad of antioxidant
enzymes in stress conditions [1].
There are a range of transcription factors acting cooperatively with NF-κB. For-
example, NF-κB and STAT3 are shown to regulate common pathways and share regu-
latory binding sites of various protective genes, while HIF and NF-κB are reported to
share common activating stimuli, regulators, and targets [61]. Indeed, the redox balance
is believed to be orchestrated by a range of transcription factors, including Nrf2, NF-κB,
activator protein 1 (AP-1), FoxO, peroxisome proliferator-activated receptors (PPARs), per-
oxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), p53, and mitogen-
activated protein kinase (MAPK; Figure 3 [91,92]). It seems likely that transcription factors
oxidants 2021, 10, x FOR PEER REVIEW 9 of 50
and vitagenes are involved in the regulation of redox status by effectively modulating the
expression and activity of ROS-generating enzymes and antioxidant enzymes [93].
Figure 3. Transcription factors andfactors

Figure 3. Transcription their clients involved
and their clients in redox homeostasis
involved regulationregulation
in redox homeostasis (adapted (adapted
from [1,92–94]).
from [1,92–94]).
NF-κB has long been considered to be a prototypical proinflammatory signaling

pathway stimulating the immune system in response to various stimuli, including physi-
cal, physiological, and/or oxidative stress. For example, NF-κB is a key target in receptor-
NF-κB has long been considered to be a prototypical proinflammatory signaling path-

way stimulating the immune system in response to various stimuli, including physical,
physiological, and/or oxidative stress. For example, NF-κB is a key target in receptor-
independent hypothalamic microinflammation [95] associated with intracellular organelle
stress, including RNA stress response [96], endoplasmic reticulum (ER) stress [97], and
defective autophagy [98]. NF-κB is involved in the regulation of many important physiolog-
ical processes; however, its overactivation has been shown to be associated with increased
risk of disease, while NF-κB suppression is associated with risk reduction [63]. Taking the
former into account, understanding the role of NF-κB signaling in stress adaptation awaits
further investigation. For example, HO-1 can improve cell protection from apoptosis by
stimulating free heme catabolism. Interestingly, the HO-1 promoter region contains an
NF-κB responsive element and, therefore, HO-1 expression is regulated by NF-κB, as well
as by other transcription factors [99]. A central role for NF-κB in regulating mitochondrial
respiration has been suggested [100]. In fact, by controlling the balance between glycol-
ysis and respiration for energy provision, NF-κB is involved in energy homeostasis and
metabolic adaptation [101]. The authors suggested to consider NF-κB as an important
checkpoint connecting cell activation and proliferation with energy sensing and metabolic
homeostasis. Since mitochondria are the main ROS source in the cell, it could be that
NF-κB signaling is involved in the regulation of ROS formation, detoxification, and the
maintenance of redox homeostasis.
4. Nrf2 and NF-kB Interplay in Oxidative Stress

Proof of the interaction and cooperative action of Nrf2 and NF-κB was taken from
experimental work with various model systems employing plant extracts, individual
compounds in vitro and in vivo, pure chemicals, and some known toxicants [6]. In our
recent review, a central role of Nrf2 in antioxidant defenses and vitagene regulation was
described in detail [27], and it seems likely that, under oxidative stress, the transcription
factors NF-κB and Nrf2 antagonize each other to coordinate a stress response [60,67,76].
For example, deletion of Nrf2 (Nrf2 knockout mice) enhanced inflammation, while Nrf2
upregulation was reported to decrease NF-kB-dependent proinflammatory and immune
responses [62]. In fact, several known Nrf2 activators are able to inhibit the NF-κB pathway.
There are many examples showing that activation and repression occur between members
of the Nrf2 and NF-κB pathways through various mechanisms [102]. Some mechanisms of
Nrf2–NF-κB interactions are summarized in Table 1.
Table 1. Possible mechanisms of Nrf2–NF-κB interactions.
Mechanisms of Nrf2–NF-κB Interactions References

Inhibiting effects of Nrf2 on NF-κB
Decreasing the intracellular ROS levels. This inhibits oxidative stress-mediated NF-κB activation [103]
Preventing the IκB-proteasomal degradation and inhibiting nuclear translocation of NF-κB. In Nrf2-deficient
cells an inhibitor of NF-kB activity (IκB) is over-phosphorylated with rapid proteasomal degradation and
[104–107]
increased NF-κB activity. Upregulation of Nrf2 induces increase heme oxygenase-1 (HO-1) levels and induce
phase II enzymes expression blocking the degradation of IκB
Reducing p50 and p65 DNA binding. Nrf2 silencing enhanced p50 and p65 DNA binding and tumour
[108]
necrosis factor (TNF)-α-induced proinflammatory gene expression
Preventing the recruitment of RNA polymerase II to start transcription of NF-κB-regulated genes. Nrf2 binds
to regulatory regions of proinflammatory genes in an antioxidant-response element (ARE)-independent [109]
manner and prevents the recruitment of RNA polymerase II to start transcription of NF-κB-regulated genes
Competition between Nrf2 and p65 for binding to the transcriptional co-activator CBP-p300 complex.
Overexpression of p65 limits the availability of CBR for Nrf2 interaction. Knockdown of p65 promotes Nrf2 [110,111]
complex formation with CBR
Degrading IKKβ through ubiquitination by Keap1 [112]
Inhibiting effects of NF-κB on Nrf2
Inactivating Nrf2 by inducing cyclooxygenase 2 [113,114]
Recruiting MAF BZIP Transcription Factor K (MafK)-associated histone deacetylase 3 (HDAC3) activity to
[115,116]
the HO-1 enhancer and deacetylating CBP leading to a suppression of its co-activator activity
Interacting with CREB-binding protein, the competent Nrf2 coactivator, and inhibiting the transcription of
[111,117,118]
genes regulated by Nrf2
Decreasing free CBP, a transcriptional co-activator of Nrf2, and promoting phosphorylation of p65.
Overexpression of p65 limits the availability of CBR for Nrf2 interaction. Knockdown of p65 promotes Nrf2 [111]
complex formation with CBR
κB sites in proximal promoter of Nrf2 are believed to be subject to binding and transcription initiation by p65 [119]
There is accumulating evidence indicating that various nutrients with antioxidant

(AO) activities could differently affect transcription factors: increasing expression of Nrf2
and simultaneously decreasing NF-κB expression and activity. This was proven in various
model systems employing plant extracts and individual polyphenolics. Firstly, in in vitro
systems, these include sinomenine [120], aloin [121], cannabisin F [122], urolithin B [123],
4-ethylguaiacol [124], gambogic acid [125], and the combination of ascorbic acid and
rutin [126]. There are also a range of in vivo studies confirming that various plant-derived
compounds, mainly polyphenols, decrease NF-κB and increase Nrf2 activity/expression
in various model systems. These include peiminine [127], hesperetin [128], oxyresver-
atrol, resveratrol and mulberroside [129], salvianolic acid A [130], naringenin [131], δ-
amyrone [132], chrysin, luteolin, apigenin, hesperetin and 30 , 40 -dimethoxy hesperetin [133],
luteoloside [134], alpinetin [135], amygdalin [136], rosmarinic acid [137], chiisanoside [138],
arbutin [139], and chicoric acid [140]. Moreover, the different direction of activation of
Nrf2 and NF-κB was also shown to be a result of exposure to various toxic compounds.
However, other agents and stimuli, including, but not limited to, ROS, LPS, flow shear
stress, oxidized low-density lipoprotein, and cigarette smoke, were reported to activate
both Nrf2 and NF-κB pathways [101,102].
The redox outcome of the NF-κB–Nrf2 interaction would depend on the activa-
tion/inhibition of various antioxidant and prooxidant enzymes. It is known that some
antioxidant enzymes are dependent on both Nrf2 and NF-κB. For example, expression of
HO-1 is shown to be regulated by Nrf2, NF-κB, and HIF-1α signaling [60,67]. On the one
hand, HO-1 was shown to possess a functional ARE that is activated by Nrf2 [141]. On
the other hand, HO-1 was shown to have a functional NF-κB site [142]. HO-1 is known
to be the stress-inducible enzyme providing AO protection in vertebrate systems, par-
ticipating in the maintenance of redox balance and being responsible for adaptation to
oxidative, inflammatory, and cytotoxic stress [25]. Similarly, a key catalytic subunit of
glutamate-cysteine ligase, the key enzyme of the cellular GSH biosynthetic pathway, also
has an ARE and can be activated by Nrf2 [143], whereas it also possesses a κB site and
can be induced by NF-κB [144]. Since GSH is a key physiological buffer responsible for
the redox homeostasis [145], regulation of its synthesis via Nrf2 and NF-κB pathways is
of great importance for redox homeostasis maintenance related to high immunocompe-
tence. Furthermore, MnSOD is also a target for both NF-κB [146] and Nrf2 [27]. It is well
established that MnSOD, a key enzyme of the first line of the AO network, is located in
mitochondria and deals with major biological ROS, namely, superoxide radicals, and it
is considered to be a major player in the establishment and maintenance of redox home-
ostasis [30]. Furthermore, glutathione peroxidase 1 (GPx1) and glutathione S-transferase
(GST) expression and activities are also under strict control by NF-κB [81] and Nrf2 [13].
The important roles of these AO enzymes in AO defense and redox homeostasis have been
previously discussed [13]. It seems likely that another redox balance regulator, namely,
thioredoxin, is also regulated by NF-κB [146,147] and Nrf2 [25]. It is interesting that HO-1,
SOD, and thioredoxins belong to the vitagene family responsible for stress adaptation and
redox homeostasis [24].
It should also be mentioned that the NF-κB pathway can induce free-radical production
via activating ROS-producing enzymes, including NADPH oxidase [148], cyclooxygenase-2
(COX-2) [102], cytochrome p450 enzymes, inducible nitric oxide synthase (iNOS), neuronal
NOS (nNOS), and xanthine oxidase/dehydrogenase [81]. The impact of such ROS produc-
tion on redox balance and adaptation to stress is still not well established; however, this
complicates the interpretation of results related to NF-κB–Nrf2 interactions in biological
systems under various stress conditions.
In many cases, activation of various transcription factors, including Nrf2, NF-κB, AP-1,
HIF-1α, p53, PPAR-γ, and β-catenin/Wnt, was associated with the oxidative stress [149].
Therefore, a complex crosstalk between Nrf2 and NF-κB pathways under various stress
conditions [62] further complicates interpretation of results related to the relative impact of
each pathway on the regulation of stress adaptation. Indeed, as mentioned above, Nrf2
and NF-κB affect each other’s expression and activity to coordinate antioxidative and
inflammatory responses; however, molecular mechanisms of this interconnection are not
yet known [62].
It is believed that condition-dependent, stress-associated changes in redox balance and
in expressions/activities of transcription factors (e.g., Nrf2/Keap1 and NF-κB/IκB/IKK)
are responsible for providing adaptive cell responses to a variety of stress stimuli through
orchestrating the optimal expression of protective target genes [150]. A hypothetical scheme
of the Nrf2–NF-κB crosstalk is shown in Figure 4.
In physiological conditions, a delicate balance between Nrf2 and NF-κB expression
in various tissues is well coordinated and maintained. It seems likely that increased NF-
κB expression as a result of low/moderate stresses can lead to a simultaneous increase
in the expression of Nrf2, leading to improved antioxidant defenses. At the same time,
decreased NF-κB expression can be observed as a feedback mechanism. This balance is
also regulated by other transcription factors and vitagenes. In the case of high oxidative
stress, when the ability of the AO defense network to deal with RONS production is
overwhelmed, the Nrf2/NF-κB balance would be broken. In such conditions, redox status
would be compromised with detrimental consequences to animal health. Furthermore, the
productive and reproductive performance of poultry and farm animals would be decreased.
Antioxidants 2021, 10, x FOR PEER REVIEW 12 of 50

stimuli through orchestrating the optimal expression of protective target genes [150]. A
hypothetical scheme of the Nrf2–NF-κB crosstalk is shown in Figure 4.
Figure
Figure 4. Hypothetical Nrf2–NF-κB
4. Hypothetical Nrf2–NF-κB crosstalk
crosstalk [1,27].
[1,27].
In physiological conditions, a delicate balance between Nrf2 and NF-κB expression

5. NF-κB in Poultry Production
in various tissues is well coordinated and maintained. It seems likely that increased NF-
The regulatory
κB expression roles of
as a result of NF-κB in poultry
low/moderate are stillcan
stresses poorly
lead understood, but accumulating
to a simultaneous increase in
information clearly indicates that, similar to mammals, NF-κB is a main regulator of many
the expression of Nrf2, leading to improved antioxidant defenses. At the same time, de-
important processes, including inflammation in avian species. In 1993, complementary
creased NF-κB expression can be observed as a feedback mechanism. This balance is also
DNA (cDNA) clones encoding the chicken NF-κB p65 subunit were isolated, and, according
regulated by other transcription factors and vitagenes. In the case of high oxidative stress,
to the information provided by the authors, chicken NF-κB can be briefly characterized as
when the ability of the AO defense network to deal with RONS production is over-
follows [151]:
whelmed, the Nrf2/NF-κB balance would be broken. In such conditions, redox status
•
wouldChicken p65 was shown
be compromised withtodetrimental
be approximately 55% identical
consequences to the
to animal mouse
health. and human
Furthermore,
p65 proteins.
the productive and Similar to its mammalian
reproductive performance counterpart,
of poultry and chicken p65 contains
farm animals wouldthe be Rel
de-
homology
creased. domain (RHD) in its N-terminal consisting of 286 amino acids and the
putative transactivation domain in its C-terminal region;
• It was
5. NF-κB inproven
Poultrythat the RHD was highly conserved between the chicken and mam-
Production
malian p65 proteins;
The regulatory roles of NF-κB in poultry are still poorly understood, but accumulat-
• The highest expression of a 2.6 kb transcript of p65 was detected in the spleen. It was
ing information clearly indicates that, similar to mammals, NF-κB is a main regulator of
also detected in other organs;
many important processes, including inflammation in avian species. In 1993, complemen-
• A fusion protein containing the RHD of chicken p65 was reported to bind to a consen-
tary DNA (cDNA)
sus kappa clones encoding the chicken NF-κB p65 subunit were isolated, and,
B-site;
according
• to the information
p65 was shown to form one provided
or more bycomplexes
the authors, chicken
with NF-κB
various canproteins,
cellular be brieflyinclud-
char-
acterized as follows [151]:
ing p50, p105, and c-Rel in chicken spleen cells [151].
• Chicken
Furthermore,p65 was
the shown to be approximately
cDNA clones encoding chicken 55%p50B/p97
identical towere
the mouse
isolatedand human
[152]. The
p65 proteins. Similar to its mammalian counterpart, chicken
amino-acid sequence of the precursor protein p97 was found to be characterized by p65 contains the Rel ho-
a
mology domain (RHD) in its N-terminal consisting of 286 amino acids
conserved structure. In particular, it was shown to have 86% identity in the RHD and lower and the puta-
(56%)tive transactivation
identity domain
in the ankyrin repeat indomain
its C-terminal
(ARD) to region;
human p50B/p97. Similar to previous
findings, expression of this gene was also found to be highest in the chicken spleen [152].
In 1995 from a chicken genomic library, a clone containing the avian I kappa B-alpha gene
was isolated [153]. Main characteristics of I kappa B-alpha can be summarized as follows:
recognizable promoter elements (i.e., TATA and CAAT boxes) were not found in avian
I kappa B-α. There were seven putative Rel/NF-kappa B binding sites in avian I kappa
B-α. When transfected into cells which produce I kappa B-α, a CAT reporter construct
containing the 50 upstream region of I kappa B-α was expressed. The regulatory elements
promoting I kappa B-α expression were identified within 1000 nt of the transcription start
site. I kappa B-alpha was shown to be found as a single-copy gene per haploid genome.
This gene was expressed in avian hematopoietic tissues and in lymphoid cells transformed
by avian reticuloendotheliosis virus [153]. It was suggested that, similar to mammals, in
chicken, p65 and c-Rel comprise components of the protein complexes that are able to
bind to the kappa B-like sequence. This binding could lead to the progressively activated
expression of the chicken lysozyme gene observed during the terminal differentiation of
macrophages [154].
In 2001, Piffat et al. constructed and characterized a composite cDNA encoding most
of the chicken RelB transcription factors [155], and their results can be summarized as
follows: within the RH domain, chicken RelB (cRelB) protein was characterized by a high
degree of sequence similarity to other vertebrate RelB proteins. However, outside this
domain, cRelB was substantially less conserved. cRelB was found to be more widely
expressed than mammalian RelB, and it was identified to have functional properties similar
to other vertebrate RelB proteins. cRelB was reported to be unable to bind DNA in a
homodimer form; however, it could form DNA-binding heterodimers with NF-kappaB p50
or p52. Overexpressed cRelB was shown to be present in the nucleus in chicken embryo
fibroblasts. The nonconserved C-terminal sequences of cRelB contained a transactiva-
tion domain found in chicken and mouse fibroblasts [155]. A new isoform of chicken
myeloid differentiation factor 88 (MyD88-2) expression was detected in a range of tissues
tested and its overexpression was found to significantly induce the activation of NF-κB
in vitro [156]. Recently the duck IKKα (duIKKα) gene was cloned and characterized. In
fact, DuIKKα was reported to encode a protein containing 757 amino acids and having
high sequence identities with the goose IKKα. Duck liver and heart were characterized
by a high expression of duIKKα messenger RNA (mRNA), while its expression was re-
ported in all tested tissues, including muscular stomach, spleen, heart, liver, lung, kidney,
cerebellum, cerebrum, windpipe, muscle, glandular stomach, thymus, duodenum, cecum,
pancreas, and bursa of Fabricius [157]. An important role of du IKKα in NF-κB regulation
has been demonstrated by increasing or inhibiting expression of duIKKα. On the one
hand, overexpression of duIKKα was shown to substantially increase NF-κB activity with
subsequent induction of cytokines interferon beta (IFN-β), IL-1β, IL-6, and IL-8 in duck
embryo fibroblasts. On the other hand, knockdown of duIKKα was found to significantly
decrease LPS-, poly(I:C)-, poly(dA:dT)-, duck enteritis virus (DEV)-, or duck Tembusu
virus (DTMUV)-induced NF-κB activation [157]. It seems likely that IKKα is evolutionarily
conserved. In fact, phosphorylation of Ser176 and Ser180 in the active center of IKKα
is believed to be vital to IKKα activation, and those Ser residues were shown to be well
conserved among mammals, birds, and fish [157].
It was shown that the NF-κB family of transcription factors contribute to activation-
induced cytidine deaminase-mediated gene conversion in chickens [158]. Gallus heat-shock
cognate protein 70 was shown to regulate RelA/p65 gene expression induced by Apoptin,
a nonstructural protein of chicken anemia virus [159]. In chicken heterophils, bacterial TLR
agonists were indicated to activate NF-κB-mediated leukotriene B4 and prostaglandin E2
production [160]. A switchlike response in NF-κB activity is based on the existence of a
threshold in the NF-κB signaling module, and phosphorylation of the Ser-578 residue of the
scaffolding protein caspase recruitment domain (CARD)-containing protein 1 (CARMA1)
was shown to account for the feedback [161]. It is known that tumor necrosis factor receptor-
associated factors (TRAFs) are responsible for activation of various signaling cascades,
being key regulatory proteins in NF-κB signaling pathways [162]. It seems likely that avian
TRAFs play important roles in defending against both RNA and DNA virus infection.
In fact, chicken TRAF3 (chTRAF3) was shown to encode a protein of 567 amino acids
with high identity to TRAF3 homologs from mammals being abundantly expressed in the
spleen, thymus, lung, and small intestine [163]. Of note, the authors showed that Newcastle
disease virus F48E9 challenge was responsible for TRAF3 suppression in chicken embryo
fibroblast cells. Recently, the full-length duck TRAF6 (duTRAF6) cDNA from embryo
fibroblasts was cloned, and it was shown that duTRAF6 was widely expressed in different
tissues. Interestingly, overexpression of duTRAF6 was found to activate NF-κB and induce
interferon-β expression [164]. It has been shown that goose TRAF6 shared similar features
with the TRAF6 of other avian species, being an essential regulator for inducing the activity
of NF-κB and playing important roles in innate immune response [165]. The amino-acid
sequence of pigeon FRAF6 (piTRAF6) was shown to share a strong identity with that
of other birds. Furthermore, piTRAF6 expression was shown in all examined tissues,
including heart, lung, spleen, thigh muscle, large intestine, caecum, kidney small intestine,
brain, bursa of Fabricius, rib, and muscular stomach [166]. The heart was characterized by
the highest level of piTRAF6 transcript, and the muscular stomach had the lowest level
of piTAF6 transcript. On the one hand, overexpression of piTRAF6 was shown to induce
NF-κB in a dose-dependent manner with increased IFN-β expression. On the other hand,
piTRAF6 knockdown was reported to suppress NF-κB activation in HEK293T cells [166].
Furthermore, the pigeon TRAF3 (PiTRAF3) gene was reported to be highly expressed in
the spleen, lung, kidney, brain, thymus, and muscle, while a moderate expression was
observed in the small and large intestines, with relatively weak expression in the heart and
liver [167].
Among the five major families of pattern recognition receptors (PRRs), Toll-like recep-
tors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs),
in particular, NOD1, recently received major attention in relation to their roles in avian
immunity via NF-κB regulation. Indeed, NF-κB is considered to be the major transcription
factor involved downstream of the TLR signaling pathway [168]. Avian TLRs are shown to
be different from their mammalian counterparts: absence of TLR8 and TLR9, along with
presence of TLR1La, TLR1Lb, TLR15, and TLR21 [169]. Therefore, in chickens, 10 TLR
receptor genes were identified: TLR1LA, TLR1LB, TLR2B, TLR2A, TLR3, TLR4, TLR5,
TLR7, TLR15 [170], and TLR21 [171]. Among them, TLR1LA, TLR1LB, TLR2A, TLR2B,
TLR4, TLR5, and TLR15 are responsible for bacterial component (lipoproteins, peptidogly-
cans, LPS, and flagellin) detection, while TLR3 and TLR7 detect viruses (double-stranded
RNA (dsRNA), single-stranded RNA (ssRNA), imidazoquinoline compounds), and TRL21
detects CpG oligodeoxynucleotides in viruses and bacteria [171]. Initially, it was reported
that chicken TLR2 and TLR4 can mediate LPS-stimulated oxidative burst, while CD14
and TLR2 are involved in the mediation of lipoteichoic acid-stimulated oxidative burst
in heterophils [172]. The tissue-specific expression of chicken TLRs (TLR2A, TLR3, TLR4,
TLR5, TLR7, TLR15, and TLR21) during embryonic development was evaluated and early
(third embryonic day) expression of all the TLR mRNAs was reported [173]. Furthermore,
TLR1 (type 1 and 2), TLR2 (type 1 and 2), and TLRs 3–5, 7, 15, and 21 were shown to
be expressed in the chicken follicular theca. The connection of the TLRs to NF-κB was
proven experimentally; the expression of IL-1β, IL-6, chemotactic and angiogenic factor
(CXCLi2), and IFN-β in tissues incubated with LPS was downregulated by an inhibitor of
NF-κB [168].
It seems likely that NF-κB is involved in the activation of avian antimicrobial peptides.
For example, chicken intestine defensins (e.g., AvBD13) were suggested to be endoge-
nous ligands for TLR4 able to enhance the proliferation of monocytes via the NF-κB
pathway [174]. It should be mentioned that cathelicidins (CATHs), short cationic host
defense peptides, also act in close concert with NF-κB. Indeed, in macrophages primed by
LPS, pigeon CATH2 was shown to act through MAPK and NF-κB signaling pathways to
enhance expression of the anti-inflammatory cytokine, while downregulating the expres-
sions of inducible nitric oxide synthase and proinflammatory cytokines and inhibiting the
TLR4 pathway [175]. Furthermore, NK-lysin/granulysin (NKL), an antimicrobial cationic
peptide expressed in natural killer cells and cytotoxic T lymphocytes, was identified in
different avian species, including chicken, turkey, zebra finch, and quail, and the 50 flanking
region of quail NKL was shown to contain two NF-κB-binding sites [176], suggesting
participation of NF-κB in regulation of NKL activity.
In hen vaginal cells, NF-κB was shown to be the transcription factor responsible for the
expression of various proinflammatory cytokines and chemokines. In fact, in response to
the ligands of TLR3, 4, and 21, increased expression of IL1B, IL6, and CXCLi2 was observed,
while IL1B expression was found in response to the ligands of TLR5 and 7 [177]. The authors
suggested that NF-κB-dependent expression of cytokines might provide the important
defense capability of vaginal tissue to bacterial and viral infections. Activation of TLR3
was shown to induce the expression of NF-κB and the production of type-I interferon [178].
IFN-κ (a type I IFN) in both chicken and duck was found to be constitutively expressed
in a range of tissues, including spleen, skin, lung, and peripheral blood mononuclear
cells (PBMCs), and it could be induced after treatment with virus in PBMCs [179]. The
duck TLR4 (duTLR4) gene was shown to be strongly expressed in the liver, kidney, spleen,
intestine, and brain [180].
Goose TLR3 was shown to be analogous to mammalian TLR3 and recognized double-
stranded RNA with subsequent activation of NF-κB [178]. In fact, the goose TLR3 gene was
shown to encode a protein containing 896 amino acids, sharing 46.7–84.4% homology with
other species with highest expression in the pancreas and lowest in the skin. The authors
showed that geese infected with H5N1 were characterized by significant upregulation
of TLR3 in various tissues, including the lung and brain [178]. The goose TLR5 (gTLR5)
gene was shown to be expressed in all studied tissues, including high expression in the
liver, spleen, and brain, moderate expression in kidney, lung, heart, bone marrow, small
intestine, large intestine, and PBMCs, and minimal expression in the cecum [181]. It was
also shown that gTLR5 can detect flagellin from Salmonella Typhimurium with subsequent
NF-κB activation in HEK293 cells. It seems likely that there is a tissue-specific regulation
of TLR expression in the process of orchestrating the immune response against bacterial
pathogens [181]. Goose TLR2-1 was also shown to play an important role in the recognition
of Mycoplasma fermentans lipopeptide, Mycoplasma gallisepticum (MG) and Salmonella
enteritidis (SE), and it induced the activation of NF-κB [182]. Furthermore, in HEK293T
cells, flagellin was shown to induce pigeon NF-κB via TLR5 activation. This was associated
with significant upregulation of IL-1β, IL-8, TNF-α, and IFN-γ. Importantly, the levels of
TLR5, NF-κB, IL-6, IL-8, chemokine ligand 5 (CCL5), and IFN-γ mRNA were significantly
upregulated as a result of flagellin stimulation of pigeon splenic lymphocytes. As could
be expected, goose TLR5 knockdown was shown to be associated with the significantly
downregulated expression of NF-κB and related cytokines/chemokines [183]. Interestingly,
the antiviral activity of pigeon IFN-α is believed to depend on the expression of NF-κB [184].
It is known that single-stranded viral RNAs and antiviral imidazoquinoline compounds
can be recognized by TLR7 with subsequent NF-κB activation. Recently, it was shown that,
in pigeon, agonist R848 (imidazoquinoline) can activate NF-κB via TLR7 [185].
It seems likely that chicken NOD1 activation in response to pathogenic invasion is
of great importance for immune defense. In partridge chicken, NOD1 was shown to be
widely distributed in various tissues, with the highest expression found in testes. Of
note, as a result of S. enterica serovar Enteritidis infection, induced expression of chNOD1,
as well as the effector molecule NF-κB, was observed in the spleen tissue [186]. Duck
NOD1 (duNOD1) was shown to be widely distributed in various organs, including heart,
liver, spleen, lung, kidney, cerebrum, cerebellum, colon, glandular stomach, thymus,
and bursa of Fabricius tissue with the highest expression found in the liver. Of note,
duNOD1 overexpression induced NF-κB, TNF-α, and IL-6 activation in duck embryo
fibroblasts (DEFs), while silencing duNOD1 was indicated to decrease the activity of NF-κB
in stimulated DEFs [187].
Chicken IL-26 was shown to regulate immune responses through the NF-κB and the
Janus kinase (JAK)-signal transducer and activator of transcription (STAT) Janus kinase
signaling pathways [188]. Similarly, chicken IL-11 was shown to bind to IL-11R and
activated the NF-κB, JAK/STAT, and MAPK signaling pathways, leading to modulation of
T helper 1 (Th1)/Th17 and Th2 cytokine production in chicken cell lines [189]. Chicken
interleukin-17B was shown to induce the NF-κB signaling pathway, leading to increased
expression of proinflammatory cytokines playing a critical role in host defense against the
bacterial pathogens [190]. In eukaryotic and prokaryotic expression systems, recombinant
chicken TNF-α was generated to demonstrate its biological activity. In particular, as a result
of binding to TNF-α receptor 1, the cytokine was shown to induce a complex signaling
cascade leading to induction of the classical NF-κB pathway [191].
In Gaoyou duck skeletal muscle (Anas platyrhynchos domesticus), NF-κB motifs (binding
sites) were identified, which are believed to be responsible for transcriptional regulation
of the slow skeletal muscle troponin I (TNNI1) gene [192]. It seems likely that chicken
NF-κB plays a central role in antiviral defense. In fact, chicken tracheal epithelial cells
were shown to initiate effective antiviral responses after stimulation with TLR ligands as a
result of interferon regulatory factor 7 (IRF7) and NF-κB signaling pathways associated
with activation of other cells, such as macrophages [193].
Receptor activator of NF-κB ligand (RANKL), a new member of the chicken TNF
superfamily, was recently identified and characterized [170]. Therefore, chicken RANKL
(chRANKL), sharing ~59–62% identity with mammalian RANKL, was shown to be ubiq-
uitously expressed in chicken tissues. In nonlymphoid tissues, chRANKL mRNA expres-
sion levels were shown to be highest in muscle, while, in lymphoid tissues, the highest
RANKL expression was found to be in the thymus, followed by the upper gut and the
bone marrow [194]. Recently identified and functionally characterized chicken leukocyte
immunoglobulin-like receptor A5 (LILRA5) was reported to activate/induce NF-κB, as
well as other immunoregulatory pathways [195].
6. Effect of Various Stress Factors on NF-κB Expression and Activity in Poultry

6.1. Thermal Stress
Continuous exposure of farm animals to an acute or gradual rise in habitat temperature
was shown to induce oxidative stress leading to reduced survivability and longevity [196],
reduced growth, decreased productive and reproductive performance, and compromised
health in poultry [197,198]. Intestinal damages due to thermal stress could lead to redox
balance disturbances and inflammatory reactions regulated via NF-κB [12]. It seems
likely that NF-κB expression in thermally stressed birds is condition-dependent, including
temperature, exposure duration, and bird’s age. On the one hand, when quails at the
age of 20 weeks were heat-stressed (34 ◦ C for 4 h per day for 20 consecutive days), liver
IL-1β and TLR4 mRNA levels were significantly increased, while NF-κB mRNA levels
were significantly decreased in comparison to the control group birds kept in normal
physiological conditions [199]. Contrary to the former, heat stress (32 ± 1 ◦ C, 6 h/day for 9
weeks) in 25 week old Roman egg-laying hens was shown to be associated with increased
serum inflammatory cytokine (IL-1β, IL-6, and TNF-α) response as compared to control
nonstressed birds. Furthermore, heat stress was also responsible for significantly increased
proliferating cell nuclear antigen (PCNA), TLR4, and NF-κB protein expression [200]. The
authors showed the protective anti-inflammatory effects of curcumin (100 and 200 mg/kg)
in the heat-stressed layers. Similarly, in black-boned chickens exposed to circular heat
stress, dietary supplementation with resveratrol (400 mg per kg) was shown to improve
intestinal integrity and ameliorate the mRNA overexpression of HSP70, HSP90, and NF-κB
on the 6th, 10th, and 15th days of stress [201].
It seems likely that cold stress can also impose oxidative stress and enhance in vivo
proinflammatory cytokine gene expression in chickens [202]. In fact, the expression of
inflammatory factors (iNOS, COX-2, NF-κB, TNF-α, and prostaglandin E synthases (PT-
GEs) were shown to be increased in chicken heart due to cold stress [203]. Under cold
stress in quail, the SOD activity decreased, reflecting an oxidative stress state, while the
mRNA expression of NF-κB increased in the duodenum, jejunum, and ileum [204]. The
inflammatory factors (COX-2, PTGEs, iNOS, NF-κB, and TNF-α) and Hsp70 mRNA levels
were shown to be increased in quail spleen as a result of the acute and chronic cold stress
(12 ± 1 ◦ C) compared with birds in the control groups [205]. Increased malondialdehyde
(MDA) content and upregulation in HSP27, HSP40, HSP70, NF-κB, COX-2, PTGEs, iNOS,
TNF-α, and IL-4 mRNAs, as well as in protein levels of HSP40, NF-κB, and iNOS, were
observed in heart due to acute cold stress (7 ◦ C for 24 h) in broiler chickens [206]. There-
fore, both heat and cold stress in poultry could be responsible for oxidative stress and
inflammation, NF-κB proven to play crucial roles in the regulation of those processes.
6.2. Mycotoxins
Mycotoxins are considered as major nutritional stress factors in poultry production [1]
imposing oxidative stress, immunosuppression [207], and low-grade inflammatory re-
sponse in the chicken intestine [44] and compromising intestinal barrier functions [208].
Among feed-contaminating mycotoxins, AFB1 is considered to be the most toxic mycotoxin.
A low level of AFB1 in broiler diet (74 µg/kg) was shown to increase the serum levels
of MDA, TNF-α, and IFN-γ. These changes were inhibited by alpha-lipoic acid (α-LA)
dietary supplementation (300 mg/kg). Interestingly, the activities of total SOD and GPx
and the expression of NF-κB p65 and HO-1 were not affected by AFB1 [209]. In a similar
experiment, an AFB1-contaminated diet (74 µg/kg) fed to chickens was associated with
upregulation of the proinflammatory cytokine IL-6 and an increase in the protein expres-
sions of both NF-κB p65 and i-NOS in the liver. Those negative effects of dietary AFB1
were shown to be inhibited by dietary alpha-lipoic acid (300 mg/kg [210]).
In an experiment with chicken feed contaminated with 1 mg/kg AFB1 fed from
day 1 until day 28, broilers exposed to AFB1 were characterized by increased serum
concentrations and mRNA expressions of TNF-α, IFN-γ, IL-1β, IL-10, and IL-6 as compared
to the control group. In addition, AFB1 caused increased degradation of the IκBα protein
and significantly elevated the phosphorylation of NF-κB (p65). Furthermore, AFB1 was
responsible for a significant reduction in the mRNA level and protein expression of the Nrf2
gene. As a result, the mRNA expression and protein expression level of Nrf2-dependent
antioxidant genes (HO-1, GPx1, NQO1, and GCLC) in the AFB1 group were shown to
be significantly downregulated [211]. Interestingly, the authors demonstrated that most
aforementioned changes in NF-κB and Nrf2-related parameters were partly alleviated by
feeding grape seed proanthocyanidin extract (250 mg/kg) simultaneously with AFB1.
6.3. Mineral Dietary Excess and Heavy-Metal Contamination

6.3.1. Mn, Cu, and NF-κB
Mn excess (600–1800 mg/kg feed) was shown to be associated with upregulated
mRNA expression of TNF-α, COX-2, NF-κB, iNOS, and NO content in chicken testis on the
60th and 90th days [212]. The inflammatory response and the mitochondrial dynamics and
apoptosis under Cu (300 mg/kg for 90 days) exposure in the heart of chickens were also
investigated. It was shown that Cu exposure induced NF-κB-mediated pro-inflammatory
cytokines, and the mitochondrial network was suggested to be considered as the cytosolic
sensor responsible for the induction of NF-κB-mediated inflammatory responses under
stress conditions [213].
In chickens, dietary Cu excess (220 and 330 mg of Cu/kg dry matter) was shown
to increase the number and area of splenic corpuscles, as well as the ratio of cortex and
medulla in the thymus and bursa of Fabricius. Furthermore, excessive Cu intake was
associated with decreased AO defenses, indicated by the reduced activities of SOD, CAT,
and GPx and increased content of MDA. There were also increased TNF-α, IL-1, and IL-1β
concentrations, upregulated mRNA levels of TNF-α, IFN-γ, IL-1, IL-1β, IL-2, iNOS, COX-2,
and NF-κB, and increased protein levels of TNF-α, IFN-γ, NF-κB, and p-NF-κB in immune
organs due to Cu toxicity [214].
6.3.2. As and NF-κB

The proinflammatory activities of As were shown in different tissues of birds, includ-
ing liver, heart, brain, muscles, and kidney. For example, in birds chronically treated with
As2 O3 , the expression levels of NF-κB and IL-6, IL-8, and TNF-α (critical mediators in
the inflammatory response) in the liver were shown to be increased [215]. Indeed, As2 O3
exposure (7.5–30 mg/kg for 90 days) led to oxidative stress, inflammatory response, and
histological and ultrastructural damage, as reflected by altered levels of cardiac enzymes in
chicken heart tissues. In addition, the messenger RNA levels of NF-κB and inflammatory
cytokines (TNF-α, COX-2, NOS, and PTGEs) significantly increased due to As2 O3 intox-
ication [216]. Similarly, when As2 O3 (1.25 mg/kg body weight (BW), corresponding to
15 mg/kg feed) was added to a basal diet and fed to male Hy-line chickens (1 day old) for
4, 8, and 12 weeks, the expression of TNF-α, NF-κB, and iNOS in chicken heart was shown
to be increased compared with the corresponding control group [217].
Arsenic (7.5, 15, or 30 mg/kg feed) was shown to increase the expression of NF-κB
and proinflammatory cytokine expression in Gallus gallus brain tissues including cerebrum,
cerebellum, thalamus, brainstem, and myelencephalon [218]. The toxic effects of arsenic
trioxide (As2 O3 , 7.5–30 mg/kg for 30–90 days) in the muscular tissues (wing, thigh, and
pectoral) of chickens were also investigated. The results showed that As2 O3 caused oxida-
tive stress as indicated by decreased activities of AO enzymes (catalase (CAT) and GPx)
and increased MDA content. There was a significant upregulation of the mRNA levels of
NF-κB and inflammatory cytokines (TNF-α, COX-2, iNOS, and PTGEs) and heat-shock
proteins (HSPs) in muscular tissue in the As2 O3 exposure groups [219]. In Hy-line chickens,
As2 O3 exposure (7.5, 15, and 30 mg/kg diet) was shown to induce oxidative stress and
inflammatory-mediated nephrotoxicity. In fact, elevated nuclear migration of NF-κB and
inflammation-related phenotypes were observed. They led to marked renal injury and
apoptosis through a mitochondrion-dependent pathway in chicken kidneys [220].
6.3.3. Cu, As, and NF-κB

Oxidative stress-induced skeletal muscle injury due to Cu2+ (300 mg/kg feed) and/or
arsenite (2.5 mg/kg BW, corresponding 30 mg/kg feed) exposure in chickens was asso-
ciated with inflammation in skeletal muscles induced via the NF-κB-mediated response
pathway. Indeed, the increased protein and mRNA levels of NF-κB and TNF-α in skeletal
muscles and the enhanced mRNA expressions of IL-1β, IL-6, and IL-12β were indicative
of proinflammatory responses occurring due to Cu and/or As exposure [221]. Arsenic
(30 mg/kg) and/or copper (300 mg/kg for 12 weeks) were shown to induce oxidative
stress, inflammation, and autophagy in chicken brains. In fact, the mRNA levels and
protein expressions of inflammation markers (NF-κB, TNF-α, COX-2, and PTGEs) were
shown to be significantly increased due to As and Cu exposure [222]. Chicken exposure
to As (30 mg/kg) and/or Cu (300 mg/kg for 4.8 and 12 weeks) was shown to lead to
oxidative stress, inflammatory response (an increase in expression of NF-κB and its down-
stream inflammation-related genes), and liver damage through mitochondrial and death
receptor-dependent pathways [223]. Arsenic trioxide (30 mg/kg) and/or copper sulfate
(300 mg/kg) were added to the chicken basal diet for 12 weeks. Significantly reduced
thymus weight and thymus index, hyperemia visible to the unaided eye, and inflammatory
cell infiltration were observed. Concurrent administration of arsenic and copper signifi-
cantly enhanced inflammation as indicated by increased levels of NF-κB, COX-2, iNOS,
PTGEs, and proinflammatory cytokines in chicken thymus. Additionally, oxidative stress
imposed by As and Cu was associated with elevation of the heat-shock protein levels [224].
Increased NF-κB expression and inflammation induction in chicken gizzard were also
shown to be a result of As2 O3 and/or CuSO4 dietary exposure [225]. Similarly, As and/or
Cu exposure in the same doses was shown to induce immunotoxicity through triggering
oxidative stress, inflammation (upregulation of NF-κB, inflammatory mediators, and proin-
flammation cytokines, accompanied by depletion of anti-inflammatory cytokines), and
immune imbalance (decreased ratio of IFN-γ/IL-4 and increased level of IL-17) in the bursa
of Fabricius of chicken [226]. In the chronic poisoning of Cu and/or As, inflammation

occurs in the chicken thalamus as indicated by increased NF-κB expression, causing ox-
idative stress (MDA accumulation) and mitochondrial damage, leading to apoptosis [227].
Excessive intake of As (1.25 mg/kg BW) and/or Cu (CuSO4, 300 mg/kg feed) for 12 weeks
was shown to lead to a significant reduction in the total antioxidant capacity (T-AOC),
catalase level, and hydroxyl radical formation in chicken brain. In addition, an increase in
the expression of HSPs and NF-κB, as well as NF-κB pathway-related proinflammatory
mediators (COX-2, TNF-α, and iNOS), due to As/Cu intoxication was observed [228].
Therefore, the proinflammatory activities of Cu and As combinations were confirmed in
the chicken liver, thymus, bursa of Fabricius, gizzard, thalamus, and brain.
6.3.4. Pb and NF-κB

Pb poisoning in chickens was shown to increase the mRNA expression of inflammation
factors (NF-κB) and HSPs in chicken livers simultaneously with the induction of NO content
and iNOS activity [229]. It was shown that Pb exposure was associated with increased Pb
content in chicken serum, induced the NF-κB pathway, and increased the expression of
selenoproteins in chicken neutrophils [230].
More data on Pb-associated modulation of the expression of NF-κB and related cy-
tokines is subsequently discussed in the Se section.
6.3.5. Cd and NF-κB

It was shown that Cd significantly induced the expression of NF-κB, leading to acti-
vation of its downstream cytokines, IL-1β, TNF-α, and IL-6, in chicken peripheral blood
lymphocytes [231]. As a result of CdCl2 (10 mg/kg feed) administration to chickens for
90 days, levels of NF-κB and phosphorylated c-Jun N-terminal kinase (p-JNK)/JNK in the
spleen increased significantly, while those of mechanistic target of rapamycin (mTOR) and
HSP70 decreased [232]. Exposure of 120 day old layers to Cd (150 mg/kg for 120 days) was
associated with oxidative stress, increased NO production, iNOS activity, and increased ex-
pression of inflammatory factors (iNOS, NF-κB, TNF-α, and PTGE) and heat-shock proteins
(HSPs 27, 40, 60, 70, and 90) in the liver tissues of birds [233]. In livers of duck exposed to a
combination of molybdenum and cadmium, mRNA expression of Hsp60, Hsp70, Hsp90,
TNF-α, NF-κB, and cyclooxygenase-2 (COX-2) was significantly upregulated [234]. Nickel
chloride (NiCl2 ) was shown to cause inflammatory responses, indicated by activation of
the NF-κB pathway and a reduction in the expression of anti-inflammatory mediators in
broiler chicken kidney [235].
Cd exposure was associated with oxidative stress as indicated by increased MDA and
reduced SOD and GPx in chicken peripheral blood lymphocytes. Interestingly, Astragalus
polysaccharide was shown to inhibit Cd-induced cytotoxicity through regulation of NF-κB
signaling [231]. It was shown that Agaricus blazei Murill polysaccharide (ABP) significantly
reduced the accumulation of Cd in the chicken spleens and reduced the expression of NF-κB
and its downstream inflammatory cytokines (IL-1β, IL-6, TNF-α, and IFN-β). Interestingly,
ABP ameliorated the Cd-induced increase in protein levels of HSPs (HSP60, HSP70, and
HSP90) in spleens. Furthermore, the activities of main antioxidant enzymes (SOD and
GPx) significantly increased, while lipid peroxidation (MDA) decreased in the ABP + Cd
group [236].
Therefore, as indicated by the above-presented data, the toxic effects of heavy metals
(As, Pb, and Cd) and Cu excess in poultry have been associated with oxidative stress and
increased expression and activity of NF-κB in various tissues, leading to inflammation. It
seems likely that usage of various protective nutrients can prevent oxidative stress and
control/decrease NF-κB expression. This can be demonstrated with plant polysaccharide
or selenium (see Section 7.1) dietary supplementation.
6.4. Other Toxic Stress Factors

Hydrogen peroxide (H2 O2 ) was shown to cause oxidative stress and impair redox
status in farm animals [237] and poultry [238]; therefore, intraperitoneal injection of H2 O2
can be used as an important model of oxidative stress in poultry.
Air quality, especially increased ammonia (NH3 ) and hydrogen sulfide (H2 S) concen-
trations, is an important factor influencing poultry health and bird performance, including
feed efficiency, growth rate, carcass quality, and susceptibility to diseases. Indeed, harmful
concentrations of NH3 and H2 S can suppress/dampen adaptive immune responses [239].
6.4.1. H2 O2
Oxidative stress in chickens induced by H2 O2 injection was shown to suppress NF-κB
signal activation and initiate autophagy in breast muscles [240]. In an experiment, Arbor
Acres chickens were grown for 42 days, and, on days 16 and 37 of growth, control chickens
were injected with saline, while experimental chickens received an intraperitoneal injection
of H2 O2 with 0.74, 1.48, and 2.96 mM/kg BW.
It was shown that the two highest doses of H2 O2 imposed oxidative stress (decreased
SOD and GPx activity), disturbed the redox balance, and significantly decreased the
expression of NF-κB and its subunits (p50 and p65) in the chicken liver on day 42, triggering
apoptosis and autophagy [241]. Indeed, H2 O2 is considered to be a central redox signaling
molecule in physiological conditions, while increased concentrations of H2 O2 (>100 nM)
can cause oxidative stress [242].
6.4.2. NH3
Ammonia was shown to increase NF-κB expression in chicken trachea, associated
with activation of downstream inflammation genes including iNOS and COX-2, reflecting
a respiratory inflammation response [243]. The NH3 -induced immunotoxic effects and
inflammatory damage of broiler spleens were associated with the Th1/Th2 imbalance,
NF-κB pathway, and compensatory response of HSPs. In particular, NH3 exposure led to
inflammatory damage, indicated by decreased inflammation-related miRNAs (miR-133a
and miR-6615), cytokines secreted by Th1 cells, and HO-1. Furthermore, the increased
expression of two target genes of the two miRNAs, three cytokines secreted by Th2 cells,
seven inflammation-related factors, and five heat-shock proteins was observed in broiler
spleens due to NH3 exposure [244]. In a broiler model of ammonia exposure, it was
shown that NH3 excess was associated with reduced breast weight and thigh weight,
histopathological changes in kidney tissues, and increased iNOS activity and NO content.
Furthermore, the mRNA and protein expression of inflammatory factors, including NF-κB,
COX-2, prostaglandin E synthases, and iNOS, increased. At the same time, T helper 1 and
regulatory T cytokines were shown to be downregulated with simultaneous upregulation of
Th2 and Th17 cytokines [245]. A study was conducted to investigate NH3 -induced inflam-
mation in chicken bursa of Fabricius and thymus. Experimental chickens were divided into
three groups: low (5.0 mg/m3 ), middle (10.0–15.0 mg/m3 ), and high (20.0–45.0 mg/m3 )
NH3 -treated chickens. In comparison to the low NH3 -treated group, high NH3 exposure
was shown to induce inflammation associated with increased nuclear debris and vacuoles
in the cortex and medulla of thymus and bursal follicles. Furthermore, reduced bursa of
Fabricius and thymus index and increased NO content and iNOS activity due to high NH3
exposure for 14, 21, or 42 days were observed. Lastly, the inflammatory cytokine contents
and mRNA levels of NF-κB, COX2, TNF-α, IL-6, IL-10, IL-1β, IL-18, TLR-2A, and iNOS
were also increased in conditions of high NH3 exposure [246].
The effect of ammonia (1 mmol/L and 5 mmol/L) on chicken splenic lymphocyte
apoptosis was studied. The results showed that NH3 exposure imposed oxidative stress,
indicated by the increased release of calcium (Ca2+ ) and ROS from mitochondria. Further-
more, an increase in the mRNA levels of GPx, inflammation-related genes (NF-κB, COX-2,
iNOS, TNF-α, and transforming growth factor-β (TGF-β)), and apoptosis-related genes
(B-cell lymphoma 2, BCL-2; Bcl-2-associated X protein, BAX; cytochrome C, Caspase-9,
and Caspase-3), and an increase in protein levels of NF-κB, iNOS, BAX, cytochrome C,
Caspase-9, and Caspase-3 were also observed due to ammonia exposure. This was also
associated with a decreased expression of GST and HO-1 in splenic lymphocytes exposed to
ammonia [247]. In chickens, the spleen tissues were seriously injured due to high ammonia
concentration (45 ppm from day 22 for 3 weeks) exposure. In the same group of birds, there
was increased expression of IL-4, IL-6, and IFN-γ and decreased expression of IL-2 in the
spleen, showing an imbalance in the Th1/Th2 response. Furthermore, the proinflammatory
factors, including NF-κB, COX-2, iNOS, and prostaglandin E (PGE), were also upregulated
in the high ammonia-exposed chickens [248].
6.4.3. H2 S
It is known that the decomposition of sulfur-containing organics in poultry houses
is responsible for the production of a large amount of H2 S, a highly toxic air pollutant,
having detrimental effects on poultry health and leading to extensive damage to the
body. In poultry, H2 S exposure is thought to damage the respiratory system and cause
an inflammatory reaction. In particular, it was shown that H2 S exposure can inhibit the
anti-inflammatory and antioxidant effects of PPAR-γ/HO-1 and activate proinflammatory
NF-κB pathway-related genes and downstream genes, leading to aggravation of pneumonia
induced by LPS. In particular, the expression of IL-4, IL-6, TNF-α, and IL-1β was increased
and that of IFN-γ decreased, and the level of PPAR-γ/HO-1 was significantly suppressed
by H2 S exposure. Furthermore, the increased expression of I-κB-β and NF-κB genes
confirmed that the NF-κB pathway was activated, with subsequent activation of COX-2,
PGE, and iNOS [249].
Fourteen day old chickens were exposed to 30 ppm H2 S for 14 days, and inflamma-
tion and oxidative stress indices were determined in the lymphocytes from peripheral
blood samples. An increase in the inflammatory response associated with upregulation
of the heat-shock proteins, NF-κB, COX-2, and iNOS was detected in the H2 S group in
comparison to the control untreated chickens [250]. Furthermore, H2 S exposure (0–3 weeks:
4 ppm, 4–6 weeks: 20 ppm of H2 S gas) was shown to induce oxidative stress and energy
metabolism dysfunction. It also led to necroptosis, activated the MAPK pathway, and
triggered the NF-κB pathway associated with a promotion of inflammatory response in
chicken spleens [251]. To study the immunotoxicity of H2 S, 1 day old broiler chicks were
exposed to atmospheric H2 S for 42 days. As a result, H2 S was shown to activate the TLR-
7/MyD88/NF-κB pathway and the NOD-like receptor protein 3 (NLRP3) inflammasome
to promote an inflammatory response, leading to tissue damage in broiler thymus and a
Th1/Th2 imbalance. In fact, H2 S was indicated to significantly induce IL-1β, IL-4, and
IL-10 levels, and it downregulated IL-12 and IFN-γ. In addition, mitochondria were shown
to be swollen, the chromatin was condensed, and nuclear structures were destroyed due to
H2 S exposure [252].
6.5. LPS-Induced Stress

The stimulating effect of LPS on NF-κB expression was shown in vitro in model sys-
tems and in vivo with poultry. For example, chicken thrombocytes responded to LPS
through TLR4, MAP kinase, and NF-κB pathways associated with increased expression
of IL-6 and cyclooxygenase-2 and enhanced production of prostaglandin E2 [253]. Simi-
larly, in chicken thrombocytes, LPS-induced IL-6 production was shown to be mediated
via activation of NF-κB, extracellular-signal-regulated kinase (ERK) 12 , and MAPK [254].
Furthermore, LPS was shown to upregulate IL-6 and CXCLi2 gene expression in chicken
heterophils via ERK1/2-dependent activation of AP-1 and NF-κB signaling pathways [255].
In laying hens, NF-κB was shown to participate in the induction of mucin expression by
LPS in the vaginal mucosa, improving barrier function against infections [256]. The LPS
challenge led to an increased mRNA abundance of TLR4, NF-κB, IL-1β, and IL-6 jejunal
mucosa of broilers. However, these effects of the LPS administration were ameliorated
by dietary Astragalus polysaccharide [257]. Salmonella LPS injection was found to induce
liver damage as indicated by increased necrotic symptoms, severe fatty degeneration,

increased alanine aminotransferase (ALT) activity, ballooning degeneration, congestion,
and increased inflammatory cell infiltration in liver sinusoids. Significant upregulation in
TLR4 expression and its downstream molecules (e.g., NF-κB, MyD88, TNF-α, IL-1β, and
TGF-β), increased apoptosis, and decreased proliferation were also observed [258]. Acute
spleen injury induced by LPS in young chicks was shown to be associated with significant
upregulation of TLR4 at 36 h post LPS stimulation and a slight increase in the expression of
NF-κB at 12 h post LPS treatment. The NF-κB-regulated cytokines (TNF-α and IL-6) were
shown also to exhibit significant upregulation at 12 h following LPS stimulation [259]. The
aforementioned data clearly indicate that LPS can activate NF-κB expression in vitro and
in vivo.
An LPS-induced ileum injury model in chickens was established, and histological
examination showed a fragmented structure of blood vessels in the ileum and presence of
necrotic tissue in the lumen in the LPS-treated chickens. In the LPS group, the structure of
the villi was chaotic with rough and uneven surface [238]. Moreover, in comparison to the
control group, LPS (60 mg/kg) induced an increase in TLR4 protein expression levels and
p65/p65 ratio, increased the mRNA expression of IL-6, IL-8, and TNF-α, and decreased
the mRNA expression of IL-10 [260]. Dihydromyricetin (DHM), a natural flavonoid com-
pound with anti-inflammatory activity (0.05% and 0.1%), was shown to have protective
effects against LPS-induced inflammatory responses, including regulation of NF-κB expres-
sion [260]. Supplementation with leonurine hydrochloride (LH), an alkaloid isolated from
Herba leonuri, attenuated LPS-induced intestinal inflammation and barrier dysfunction by
significantly downregulating the mRNA expression of NF-κB, COX-2, and proinflammatory
cytokines (TNF-α, IL-1β, and IL-6) in the jejunal mucosa. Furthermore, LH administration
attenuated LPS-induced IκBα phosphorylation and nuclear translocation of NF-κB (p65) in
the jejunal mucosa [261].
6.6. Diseases
Modern breeds/strains of commercially grown meat-type broiler chickens are char-
acterized by increased body weight, improved meat yield, including the Pectoralis major
(breast) muscle, improved feed conversion, and decreased time to processing. However,
myopathies affecting meat quality, especially in the Pectoralis major muscle, are considered
as a major challenge for modern broiler production. It seems likely that broiler breast
muscle myopathies are associated with inflammation [262]. The NF-κB signaling pathway
was found to be induced, the mRNA expression levels of downstream inflammatory medi-
ators were increased, and TLR levels were upregulated in Pectoralis major of Wooden breast
myopathy-affected broiler chickens [263]. The authors also showed that, in the serum of
broilers with breast myopathies, contents of IL-1β, IL-8, and TNF-α were increased. At the
same time, in breast muscle, the mRNA expression of inflammatory cytokines was dys-
regulated, showing association of this myopathy with an immune disorder and systemic
inflammation response.
The regulatory roles of NF-κB in the development and pathogenesis of various bac-
terial and virus diseases were recently studied. In particular, the roles of NF-κB and
inflammation in the pathogenesis of pathogenic Escherichia coli, various Salmonella species,
and Mycoplasma gallisepticum, Eimeria tenella and Clostridium perfringens have received the
most attention among bacterial diseases. Infectious bursal disease and Newcastle disease
were on the frontline for understanding roles of inflammation and NF-κB in their pathology.
6.6.1. Escherichia coli

Escherichia coli is known to be a Gram-negative, facultative anaerobe bacterium be-
longing to the Enterobacteriaceae family [264]. Certain E. coli strains, known as “avian
pathogenic E. coli” (APEC) are responsible for colibacillosis, one of the most important
causes of chicken mortality in the poultry industry worldwide [265]. To explore the host–
pathogen interaction, a response in global gene expression profiling of chicken type II
pneumocytes (CP II cells), responsible for secreting surfactants and modulating lung im-
munity, to avian pathogenic Escherichia coli (APEC-O78) infection was determined. In
fact, CP II cells were shown to respond to APEC infection with marked changes in the
expression of 1390 genes (from 18,996 genes identified) with 803 downregulated mRNAs
and 587 upregulated mRNAs [266]. The major enriched pathways were identified to be
related to the NF-κB signaling pathway, apoptosis pathway, tight junction, and cytokine–
cytokine receptor interaction. Furthermore, the top 15 upregulated biological process terms
were found to include regulation of the Toll signaling pathway, apoptotic process, and
intracellular signal transduction [244]. The expression of phosphorylated NF-κB p65 and
phosphorylated IκB was significantly upregulated in the APEC-infected chicken type II
pneumocytes compared with the control group. However, baicalin, a medicinal ingre-
dient isolated from dry roots of Scutellaria baicalensis Georgi, was shown to significantly
inhibit the expression of phosphorylated NF-κB p65 and phosphorylated IκB induced by
APEC-O78 [267].
Furthermore, the protective effects of baicalin on avian pathogenic APEC-induced
acute lung injury associated with NF-κB activation and inflammation in chicken were
shown [268]. Artemisinin, a drug derived from the Asian plant Artemisia annua, was shown
to alleviate Eimeria tenella infection in chickens as a result of facilitating the apoptosis of
host cells and suppressing the inflammatory response by suppressing the increased mRNA
expressions of NF-κB and interleukin-17A in ceca during infection [269]. Schizandrin, a
group of bioactive chemical compounds found in Schisandra chinensis, was shown to atten-
uate inflammation induced by APEC-O78 in chicken type II pneumocytes by decreasing
the levels of IL-1β, IL-8, IL-6, and TNF-α via its inhibitory effect on NF-κB and MAPK
activation [270]. Dietary treatment with both live yeast and mannan oligosaccharide was
shown to alleviate E. coli-induced increases in ileal Toll-like receptor 4, NF-κB, and IL-1 β
expression in broilers [271].
6.6.2. Salmonella
Salmonella, a Gram-negative bacterium belonging to the Enterobacteriaceae family, is
commonly found in the digestive tract of infected chickens. Furthermore, it is an impor-
tant cause of foodborne human illnesses worldwide, and poultry meat is reported to be
responsible for up to 25% of outbreaks caused by foodborne pathogens [272]. Infection
of chicken TLR5 transfected cells with Salmonella enterica serovar Enteritidis was shown
to activate NF-κB in a dose- and flagellin-dependent fashion [273]. In order to study the
role of NF-κB in the signal transduction pathway of the Salmonella enteritidis-challenged
cells, chicken macrophage HD11 cell line and small interfering RNAs (siRNA), specif-
ically inhibiting NF-κB1 expression, were used. In particular, it was found that a 36%
inhibition of NF-κB1 expression was associated with increased gene expression of both
TLR4 and IL-6 at both 1 h and 4 h following Salmonella challenge [274]. TLR4 was shown
to activate NF-κB signaling during cerebral ischemia–reperfusion, leading to increased
secretion of inflammatory cytokines and damage of brain tissue [275]. Nucleotide-binding
oligomerization domain-containing protein-1 (NOD1), known as a cytoplasmic pattern
recognition receptor (PRR), is considered to be a key member of the NOD-like receptor
(NLR) family. As a result of recognition of various pathogens by NLRs, NF-κB signaling is
modulated, leading to induction of the host innate immune response. In fact, following
S. enterica serovar Enteritidis infection, induced expression of chicken NOD1 and NF-κB
was demonstrated [186]. In carrier chickens challenged with Salmonella enterica serovar
Pullorum, upregulation of NF-κB and NRLC5 signaling pathways at different persistence
periods was observed [276].
The Salmonella secreted factor L, a deubiquitinase that contributes to the virulence of
Salmonella Typhimurium, was shown to suppress the intracellular NF-κB pathway associ-
ated with enhancement of the virulence of Salmonella Pullorum in a chicken model [277]. In
chickens, Salmonella Typhimurium was shown to significantly reduce chicken performance,
including the feed intake and body weight gain, detrimentally affecting the feed conversion
ratio. At the same time, Salmonella infection induced the inflammatory expressions of NF-
κB and MyD88 genes and decreased the expressions of claudin-1, occludin, and mucin-2
tight junction genes in the intestines. Furthermore, S. Typhimurium was reported to signif-
icantly decrease ileal bacterial diversity indices [278,279]. The invasion plasmid antigen J
(IpaJ) from Salmonella Pullorum was reported to suppress NF-κB activation by inhibiting
IκBα ubiquitination and modulating the subsequent inflammatory response [280].
6.6.3. Mycoplasma gallisepticum

Mycoplasma gallisepticum (MG), an avian pathogen, belonging to the class of Molli-
cutes, is known as the primary etiological agent of chicken chronic respiratory disease,
causing inflammatory damage of the host respiratory system [281]. Initially, when live
MG bacteria were incubated with primary chicken tracheal epithelial cells, inflamma-
tory NF-κB-dependent genes were upregulated, while an NF-κB inhibitor abrogated the
inflammatory response [282]. Furthermore, TLR2-2 and TLR6 were reported to be upreg-
ulated upon MG infection, followed by induction of the NF-κB-mediated inflammatory
responses [283]. At the next stage of the research related to the relationship between MG
infection and NF-κB expression, microRNas were employed. Indeed, noncoding RNAs,
including microRNAs (miRNAs), are known to be involved in the regulation of various
cellular processes including gene expression at the post-transcriptional level [284]. Among
them, MiR-21 is an evolutionarily conserved miRNA found in a wide range of vertebrate
species, including mammals and birds [285].
Recently, it was shown that, in order to provide an effective defense against MG
infection, gga-miR-21 is involved in the activation of MAPKs and NF-κB signaling path-
ways, leading to increased production of inflammatory cytokines and suppressing cell
apoptosis [286]. Similarly, upon MG infection, gga-miR-146c upregulation was shown
to repress MMP16 expression and activate the TLR6/MyD88/NF-κB pathway. This was
associated with inhibiting cell apoptosis and promoting cell proliferation, important events
to defend against host MG infection [287]. Furthermore, upregulating gga-miR-16-5p
was reported to decrease multiplication and cycle progression and increase apoptosis of
MG-infected DF-1 cells, by inhibiting the phosphatidylinositol 3-kinase (PI3K)/protein
kinase B (Akt)/NF-κB pathway to exert an anti-inflammatory effect [288]. In a model
system with DF-1 cells in chicken embryo fibroblasts, gga-miR-146c was shown to acti-
vate the TLR6/MyD88/NF-κB pathway through targeting matrix metalloproteinase-16
(MMP16) to prevent MG infection in chickens [287]. Upon MG infection, upregulation
of miR-130b-3p was shown to activate the PI3K/Akt/NF-κB pathway and induce cell
proliferation as a result of downregulating phosphatase and tensin homolog (PTEN). Im-
portantly, inhibition of miR-130b-3p led to the opposite results [289]. In DF-1 cells exposed
to Mycoplasma gallisepticum, lipid-associated membrane proteins were reported to induce
IL-1β production through the NF-κB pathway [290]. Indeed, MG infection was shown to
trigger an inflammatory response through the TLR-2/MyD88/NF-κB signaling pathway,
leading to tissue damage in chicken thymus [43,291].
Polydatin (PD), a resveratrol glycoside isolated from Polygonum cuspidatum, with
prominent anti-inflammatory activity, was used as a therapeutic means against MG-
induced inflammation in chickens. First, histopathological studies clearly showed that PD
treatment (15, 30, and 45 mg/kg) was able to alleviate MG-induced pathological changes
in the chicken embryonic lung. Second, PD treatment (15, 30, and 60 µg/mL) was shown
to significantly suppress the expression of IL-6, IL-1β, and TNF-α induced by MG in
chicken embryo fibroblast (DF-1) cells. Furthermore, the MG-induced levels of TLR6,
MyD88, and NF-κB were also significantly decreased by PD treatment, which restrained
the MG-induced NF-κB-p65 nuclear translocation [292].
As mentioned above, MG can target host cells and cause chronic respiratory disease
in chicken. In fact, in chicken spleen and DF-1 cells, MD infection was shown to impose
oxidative stress and inflammation. However, baicalin was reported to suppress TLR2–NF-
κB signaling pathway by inhibiting the phosphorylation of p65 and IκB [293]. Interestingly,
baicalin was reported to restore the mRNA expression of mitochondrial dynamics-related

genes and maintain the balance between mitochondrial inner and outer membranes, as
well as upregulate the Nrf2/HO-1 pathway and suppress the NF-κB pathway in the spleen
of MG-infected chicken [294]. Similar protective effects of baicalin [295] and polydatin,
a resveratrol glycoside isolated from Polygonum cuspidatum [292], against MG-induced
inflammation injury in chicken embryonic lung were associated with their inhibition of the
TLR6/MyD88/NF-κB pathway.
Puerarin (PUE), an isoflavone found in a number of plants and herbs, was shown to
inhibit MG-induced inflammation and apoptosis via suppressing the TLR6/MyD88/NF-κB
signal pathway in chickens. In fact, compared to the MG-infected group, PUE was found
to effectively inhibit the expression of MG-induced inflammatory genes, including TNF-α,
IL-1β, IL-6, TLR6, MyD88, and NF-κB. In particular, PUE was reported to dose-dependently
inhibit MG-induced NF-κB p65 translocation to the cell nucleus [296].
6.6.4. Eimeria tenella

Chicken coccidiosis is an enteric disease caused by Eimeria infection, leading to severe
economic losses associated with immunosuppression and a high level of mortality in
the poultry industry worldwide [297]. In fact, Eimeria tenella infection was shown to
significantly increase the expression of NF-κB mRNA in chicken cecal tissue in vivo [269],
and a similar increase in the expression level of NF-κB was observed in chicken intestinal
epithelial cells in vitro after infection with E. tenella sporozoites [298].
There is a need for more research related to the regulatory roles of NF-κB pathway in
the development of a chicken coccidiosis prevention strategy.
6.6.5. Clostridium perfringens

Clostridium perfringens-induced necrotic enteritis in chickens has become an economically
significant problem for the broiler industry [299,300], especially at farms that have stopped
the use of antibiotic growth promoters [301]. It is known that the Clostridium perfringens main
cell-wall component, peptidoglycan, can be recognized by TLR2 with subsequent activation
of the NF-κB signaling pathway to induce cytokine and chemokine production, leading to
inflammation [302]. The authors conducted an in vitro study with primary intestinal epithelial
cells to assess the chicken intestinal inflammatory responses to C. perfringens and showed
increased cytokine expression related to NF-κB activation [302]. Furthermore, pathways
affected by the infusion of C. perfringens culture supernatant in the duodenum of broilers
included NF-κB signaling, death receptor signaling, and an inflammatory response [303].
Importantly, two Lactobacillus species were shown to reduce the growth of
Clostridium perfringens and inhibit the upregulation of NF-κB p65 in C. perfringens-challenged
chicken intestinal epithelial cells [304]. Indeed, inclusion of L. acidophilus into the chicken
diet was shown to improve gut health and reduce the mortality of Clostridium-challenged
broiler chicks suffering from necrotic enteritis [305].
6.6.6. Chlamydia psittaci

Chlamydia psittaci, a pathogen in poultry and pet birds, is known to have some protec-
tive mechanisms to cope with proinflammatory mediators during the early host response,
leading to effective evasion and causing psittacosis/ornithosis [306]. The polymorphic
membrane protein D (PmpD) is known as a highly conserved outer-membrane protein
helping the pathogen to decrease immune system protection during Chlamydia psittaci
infection. Therefore, the ability of the N-terminus of PmpD (PmpD-N) to regulate the
functions of chicken macrophages was studied. In particular, it was shown that stimulation
of HD11 macrophages with PmpD-N was associated with an increased secretion of the
Th2 cytokines, IL-6, and IL-10 and upregulated expression of TLR2, TLR4, MyD88, and
NF-κB. In great contrast, inhibition of TLR2, MyD88, and NF-κB in HD11 cells was re-
ported to significantly decrease IL-6 and IL-10 cytokine levels associated with significantly
enhanced NO production and phagocytosis [307]. The plasmid-encoded protein CPSIT_P7
of Chlamydia psittaci was shown to induce the TLR4/Mal/MyD88/NF-κB signaling axis

and orchestrate the inflammatory cytokine response [308].
It is important to mention that, during host cell infection, NF-κB is activated by various
pathogens, leading to the creation of a hostile environment for invading infectious agents;
however, the pathogen can diminish the protective inflammatory response by blocking
NF-κB translocation to the nucleus [309].
6.6.7. Infectious Bursal Disease

As mentioned above, NF-κB is involved in the pathogenesis of various virus-induced
diseases. In fact, infectious bursal disease virus (IBDV) is known as the etiological agent of
a highly transmissive and immunosuppressive disease detrimentally affecting domestic
chickens (Gallus gallus) in commercial poultry production. Indeed, IBD (Gumboro disease)
can cause high morbidity and mortality of infected birds, leading to major economic losses
in the poultry industry worldwide. The danger of IBD is associated with its immunosup-
pressive action associated with a loss of IgM-bearing B lymphocytes and the destruction of
the bursa of Fabricius [72]. There is some evidence indicating that IBDV infection can cause
oxidative stress in chickens [310], but regulatory roles of the antioxidant defense network
in IBD need further elucidation.
IBDV infection was found to induce spleen macrophage activation via p38 MAPK and
NF-κB pathways [311]. However, the molecular mechanisms of IBDV development and
pathogenicity are still poorly understood; nevertheless, poorly regulated cytokine produc-
tion and B-cell depletion due to apoptosis are believed to be important contributing factors
to the disease pathology and severity. In IBDV-infected chicken embryonic fibroblasts, a
great number of target genes and inducers of NF-κB were reported to be upregulated, in
comparison to noninfected cells. It could well be that IBDV may support its replication
and facilitate viral spread by affecting host-cell survival and apoptosis through NF-κB
activation [312]. Interestingly, exacerbated apoptosis of cells infected with IBD virus upon
exposure to IFN-α was shown to be associated with double-stranded RNA-dependent
protein kinase (PKR), TNF-α, and NF-κB expression. Indeed, their downregulation is
reported to drastically reduce the extent of apoptosis [313]. Protocatechuic acid (PCA), a
type of widely distributed naturally occurring phenolic acid, was found to activate NF-κB
signal pathways in the early stage of IBDV infection, leading to apoptosis promotion [314].
6.6.8. Newcastle Disease

Newcastle disease (ND) is regarded as one of the most important avian diseases signif-
icantly affecting poultry production all over the world, being a great threat to the poultry
industry [315]. It is well known that ND epidemics can cause high chicken mortality with
great economic losses [315]. There is no effective treatment for the disease, and poultry
producers rely on vaccination and strict biosecurity as vital measures for controlling the
spread of the disease [316]. It is known that NDV can cause oxidative stress in poultry [310];
however, the roles of redox homeostasis in ND development are poorly understood. In
fact, intense inflammatory responses leading to excessive cellular apoptosis and tissue
damage were shown to be a result of Newcastle disease virus (NDV) infection in poultry.
However, the molecular mechanisms of such actions have not been fully elucidated [317].
In NDV-infected chickens, glucocorticoid dexamethasone was shown to modulate NF-κB-
dependent gene expression by upregulating FK506-binding protein 51 expression [318].
Furthermore, Newcastle disease virus-like particles were shown to induce dendritic cell
maturation with synthesis of proinflammatory cytokines through the TLR4/NF-κB path-
way [319]. Recently, it was shown that, during NFV infection, high-mobility group box
1 (HMGB1), a key member of the damage-associated molecular patterns (DAMPs), was
responsible for NF-κB induction and a drastic increase in proinflammatory cytokine pro-
duction in DF-1 and A549 cells [317]. It seems likely that activated NF-κB signaling can
suppress NDV replication. This was shown experimentally with DF-1 cells (e.g., a chicken
embryo fibroblast cell line) by using gga-miR-19b-3p, which enhanced NF-κB activity and
led to increased inflammatory cytokine production and inhibition of NDV replication [320].
Expression of IFIT5 (interferon-induced protein with tetratricopeptide repeats 5) pos-
sessing antiviral activity and enhancing innate immunity was studied in chickens. The
relative mRNA expression level of chicken IFIT5 (chIFIT5) was shown to be the highest
in spleen, and the expression level of chIFIT5 was found to be significantly upregulated
following NDV infection. In particular, it was shown that overexpression of chIFIT5 could
promote IRF7- and NF-κB-mediated gene expression following NDV infection [321]. The
DNA-sensing pathway is known to induce innate immune responses against DNA virus
infection, with NF-κB signaling being critical for the establishment of innate immunity.
6.6.9. Other Viral Diseases

It seems likely that Marek disease virus (MDV) and reovirus infections also affect
NF-κB signaling. In fact, Marek’s disease (MD) is a neoplastic virus disease infecting
chickens and frequently causing cancers in animals [322]. It was shown that NF-κB is
involved in MDV-induced neoplastic transformation of CD30-expressing chicken lym-
phocytes in vivo [323]. Furthermore, chicken MD virus RLORF4 (a MDV-specific gene)
was shown to inhibit type I interferon production by antagonizing NF-κB activation. In
fact, RLORF4 binds to the Rel homology domains of the NF-κB subunits p65 and p50,
interrupting their translocation to the nuclei and, thus, inhibiting IFN-β production [324].
Avian reoviruses are important pathogens causing infectious arthritis/tenosynovitis,
stunting syndrome, respiratory disease and enteric disease, immunosuppression, and
malabsorption syndrome in poultry [325,326]. Thus, avian reovirus can cause oxidative
stress and disturb redox homeostasis in poultry [310]. Avian reovirus S1133 in cell cultures,
in the early stages of infection, was shown to induce Akt/NF-κB and STAT3 signaling,
leading to an inflammatory response and delayed apoptosis [327]. Furthermore, in avian
reovirus-infected chickens, the expression peak for NF-κB in peripheral blood lymphocytes
was shown to occur at 3 days post infection (dpi). Similarly, IFN-α, IFN-β, and IL-12
expression levels also peaked at 3 dpi, while IFN-γ, IL-6, IL-17, and IL-18 expression
reached a maximum level earlier (at 1 dpi), whereas IL-8 (5 dpi) and IL-1β and TNF-α (7 dpi)
peaked later [328]. Recently, the phosphoproteomic responses of duck to reovirus infections
in the spleen tissue were studied, and 16 proteins involved the intracellular signaling
pathways of PRRs were shown to be phosphorylated proteins. In particular, changes in the
phosphorylation levels of NF-κB, as well as MyD88, receptor interacting protein 1 (RIP1),
MDA5, and IRF7, indicated an important role of protein phosphorylation in duck immune
responses to viral antigens [329]. Pattern recognition receptor signaling during innate
responses to influenza A viruses in the mallard duck was recently reviewed [330], and the
fundamental roles of NF-κB in innate immune responses to duck Tembusu virus infection
were discussed in detail [331].
As can be seen from the above-presented data, NF-κB plays a pivotal role in poul-
try protection against major microbial and viral diseases, by regulating immunity and
inflammation; however, the molecular mechanisms of its regulation in avian species await
further investigation.
7. Nutritional Modulation of NF-κB in Poultry

7.1. Selenium
There is a great body of evidence indicating that the micronutrient selenium (Se)
and selenoproteins are involved in the regulation of inflammatory signaling pathways,
including NF-κB signaling, implicated in the pathogenesis of various diseases [13,332]. As
a part of 25 selenoproteins, Se is involved in antioxidant defenses and the maintenance of
redox balance [13].
The literature data related to the effect of Se on NF-κB and inflammation can be
divided into three groups. Firstly, the detrimental effects of Se deficiency or excess on
NF-κB signaling were shown. Secondly, the protective effects of Se in Pb and Cd toxicity
were described. Thirdly, in LPS-induced models of oxidative stress and inflammation, Se

was shown to be protective.
7.1.1. Se Deficiency
Se deficiency in chickens was shown to lead to activation of the NF-κB pathway,
with a change in selenoprotein gene expression resulting in kidney dysfunction [333].
Furthermore, Se deficiency was reported to attenuate chicken duodenal mucosal immunity
via activation of the NF-κB signaling pathway. In particular, Se deficiency enhanced the
phosphorylation of IκB-α and phosphorylation of kappa-B kinase subunit alpha (IKKα),
as well as increased p50 and p65 DNA-binding activities. Furthermore, in Se deficiency,
IKKα was elevated, but IκB-α was decreased [334]. The increasing levels of ROS in chicken
duodenal mucosa due to Se deficiency could trigger NF-κB signal transduction [335]. In
a recent experiment, the control group was fed a complete formula feed (0.2 mg Se/kg),
while the experimental group of chickens was fed a self-made low-Se diet (0.004 mg/kg)
for 15, 25, 35, 45, and 55 days. In chicken spleen at 15–45 days, the relative expression
of TLR4 mRNA was shown to be increased due to Se deficiency. The relative expression
of NF-κB mRNA in the experimental group was also increased in comparison to that in
the control group at 15–45 days. The relative expression of IL-6 mRNA and the protein
expression level of TLR4 in the experimental group were increased due to Se deficiency
at 15–45 days of age [336]. The authors concluded that Se deficiency is associated with
inflammatory injury as a result of the TLR4/TIR-domain-containing adapter-inducing
interferon-β (TRIF)/NF-κB signaling pathway activation in chicken spleen.
Interestingly, the adverse effects of Se excess/toxicity (15 mg/kg Se for 45 days)
on inflammatory and immune responses in chicken spleens were also associated with
enhancement of the expression of NF-κB, iNOS, COX-2, PTGE, IL-6, TNF-α, and IL-4, but a
depression of FOXP3 and IFN-γ [337]. However, Se dietary supplementation at 2 mg/kg
did not affect the mRNA levels of NF-κB, COX-2, PTGEs, and TNF-α in chicken kidneys.
7.1.2. Se and Pb Toxicity

Dietary Se has been proven to alleviate the Pb-induced increase in NF-κB and HSP
expression in chicken livers [229]. Importantly, Se supplementation (1 mg/kg diet) was
shown to reduce Pb concentration in serum, partly mitigated the effect on the activation
of the NF-κB pathway, and further enhanced selenoprotein expression induced by Pb
exposure [230]. One week old male chickens were treated via drinking water with Pb
(350 mg/L) and provided with dietary Se (1 mg/kg) or both Pb and Se. On the 4th, 8th, and
12th weeks, kidneys were used to assess oxidative stress indicators, relative expressions
of cytokines, and other inflammatory factors. The results showed that Pb consumption
imposed renal injuries associated with increased lipid peroxidation (MDA), as well as the
content and expression of IL-1β, IL-6, IL-17, NLRP3, caspase-1, NF-κB, COX-2, TNF-α, and
PTGEs, and with reduced GSH content, as well as GPx and SOD activities, in the chicken
kidneys. Se administration was shown to alleviate the aforementioned changes [338].
Pb treatment (50 mg/kg for 90 days) was shown to compromise AO defenses by
inhibiting the activities of SOD, GPx, and CAT, causing the accumulation of NO and MDA,
leading to oxidative stress, which promoted the expression of MAPK/NF-κB pathway
genes (ERK, JNK, P38, NF-κB, and TNF-α) and activated HSPs (HSP27, HSP40, HSP60,
HSP70, and HSP90) in chicken spleen. However, Pb-caused necroptosis was inhibited by
Se (2 mg/kg) co-treatment [339]. Selenium (sodium selenite, 1 µM) was shown to prevent
lead (30 µM)-induced necroptosis by restoring antioxidant functions (SOD, GPx, CAT) and
blocking the MAPK/NF-κB pathway (decreasing the expression of NF-κB and TNF-α) in
chicken lymphocytes [340].
7.1.3. Se and Cd Toxicity

Dietary Cd (150 mg/kg for 90 days) was shown to increase the mRNA levels of NF-κB,
COX-2, PTGEs, and TNF-α in chicken kidney. Interestingly, Se partly ameliorated the
proinflammatory effects of Cd dietary supplementation [341]. Similarly, treatment with Se

(2 mg/kg for 90 days) significantly alleviated Cd-induced hepatic toxicity (150 mg/kg) in
laying hens, as evidenced by a reduction in Hsp60, Hsp70, Hsp90, NF-κB, COX-2, PTGEs,
TNF-α, and IL-1β expression [342].
Chicken Cd exposure (150 mg/kg) was shown to activate inflammation-related genes
including TNF-α, NF-κB, iNOS, COX-2, and prostaglandin E synthase (PTGEs) in chicken
breast muscles [323,343]. Interestingly, Se (2 mg/kg as sodium selenite for 90 days) was
reported to alleviate Cd-induced inflammation and meat quality deterioration via antiox-
idant and anti-inflammation action [343]. Supplementation with Se-yeast (0.5 mg/kg)
was shown to have an antagonistic effect on Cd-induced inflammatory injury in chicken
livers [233].
7.1.4. Se and LPS

By inhibiting the phosphorylation of NF-κB, Se was shown to reduce breast tissue
inflammatory injury induced by LPS [344]. In laying hens, LPS stimulation (injected LPS
into the abdominal cavity at the age of 8 months) imposed oxidative stress, indicated by
decreased activity of SOD, GPx, and CAT, decreased GSH content, and increased H2 O2
and MDA content in the chicken myocardium. LPS also increased the expression of p38
MAPK and NF-κB, as well as TNF-α, IL-1, PTGE, COX-2, and iNOS. Interestingly, the
addition of dietary SeMet (0.5 mg/kg for 4 months) was found to alleviate the changes in
the above inflammation indicators [345]. Similarly, SeMet (0.5 mg/kg) was shown to inhibit
the LPS-induced inflammation of liver tissue via suppressing the TLR4–NF-κB–NLRP3
signaling pathway in chickens [346].
In a recent experiment with 46 week old ISA laying hens, birds were injected with LPS
(200 mg/kg) intraperitoneally, and, after 5 h, the tracheal tissue was collected for various
assays. In the LPS-treated group, the epithelial cells were shown to be degenerated with
necrotic changes accompanied by inflammation. The expression of the NF-κB pathway
and related inflammatory factors, including TNF-α, iNOS, NF-κB, COX-2, and PTGEs,
was significantly increased in the trachea tissue due to LPS treatment. In such conditions,
increased (from 0.2 up to 0.5 mg/kg) SeMet supplementation for 90 days showed anti-
inflammatory effects [347].
7.2. Amino Acids

Dietary L-arginine supplementation (1.05–1.9%) was shown to attenuate the LPS-
induced inflammatory response in broiler chickens, as evidenced by the decreased ex-
pression of IL-1β, TLR4, and PPAR-γ mRNA in the spleen, and IL-1β, IL-10, TLR4, and
NF-κB mRNA in the cecal tonsils [348]. There were no significant interactions between
immune stress caused by bovine serum albumin (BSA) and supplementation of threonine
(0.49–0.76% for 21 days) for NF-κB gene expression in the jejunum or ileum of Pekin
ducks [349].
Interestingly, NF-κB expression in the jejunum was twofold higher than that in the
ileum. Leucine was reported to alleviate LPS-induced inflammatory responses as a result
of downregulating the NF-κB signaling pathway. In particular, a model system employing
the intestinal tissue from specific pathogen-free chick embryos cultured in the presence
of LPS for 2 h was used. LPS was shown to increase the phosphorylation of NF-κB while
decreasing the phosphorylation level of mTOR. In this system, leucine supplementation at
40 mM was reported to suppress the phosphorylation levels of NF-κB, while restoring the
phosphorylation level of mTOR [350].
7.3. Phytogenic Supplements

Recently, various phytogenic supplements received tremendous attention in poul-
try and animal nutrition, and the molecular mechanisms of their protective actions in
many cases were related to their antioxidant properties. However, our analysis of the
current data in this area showed that polyphenolic compounds are poorly absorbed and
their concentrations in target tissues are several orders lower than those used in in vitro
studies [351]. Furthermore, their antioxidant properties are condition-dependent, and, in
many cases, polyphenols could show pro-oxidant activities. Therefore, it was suggested
that the polyphenolic effects on NF-κB and Nrf2 expression could be a major molecular
mechanism of their protective action in various model systems and in poultry nutrition in
general [351,352]. Data presented in Section 4 showing the activation effects of polyphenol
compounds on Nrf2 expression and activity with simultaneous suppression of the NF-κB
pathway confirmed that idea. There are also a range of publications showing protective
effects of phytogenic supplements in poultry nutrition under various stress conditions.
In chickens receiving conventional vaccinations, the NF-κB gene mRNA relative
expression in hepatocytes linearly decreased as a result of increasing resveratrol, a plant-
derived polyphenolic compound, with a dietary concentration from 200 to 800 mg/kg
of diet [353]. Similarly, dietary resveratrol (200–600 mg/kg) was shown to reduce the
protein expression of NF-κB, HSP70, and HSP90 in the jejunal chicken villi after 15 days of
heat stress [201]. Dietary resveratrol (400 mg/kg) was also shown to protect quail hepato-
cytes against heat stress by decreasing the expression of NF-κB, Hsp70, and Hsp90, and
increasing the hepatic and SOD, CAT, and GSH-Px activities [354]. Daidzein (DA), a soy
isoflavone, included into the breeder diet at 20 mg/kg was shown to activate the NF-κB,
MAPK, and Toll-like receptor signaling pathways of the offspring broilers. Furthermore,
DA promoted lymphocyte development and differentiation and downregulated the expres-
sion of genes regulating lymphocyte apoptosis. It also increased the proportion of B cells,
leading to promotion of Ig secretion with increased serum IgA and IgG levels and serum
ND virus antibody titers [355]. In healthy Arbor Acre broilers, quercetin supplementation
(0.04% and 0.06% for 6 weeks) was shown to significantly increase the expression of TNF-α,
TNF receptor associated factor-2 (TRAF-2), TNF receptor superfamily member 1B (TN-
FRSF1B), nuclear factor kappa-B p65 subunit (NF-κBp65), and interferon-γ (IFN-γ) mRNA,
while expression of NF-κB inhibitor-alpha (IκB-α) mRNA was significantly decreased [356].
Ginsenosides, the major constituents of ginseng with unique biological activities, were
shown to promote proliferation of chicken primordial germ cells through protein kinase C
(PKC)-involved activation of NF-κB [357].
Tanshinone IIA (TIIA), a major lipophilic component extracted from the root of
Salvia miltiorrhiza Bunge used in Chinese medicine, was shown to have a protective effect
against pulmonary arterial hypertension-related inflammatory responses [358]. Treatment
with an extract of Hypericum perforatum L., also known as Saint John’s wort, at doses of
480–120 mg/kg for 5 days was shown to reduce infectious bronchitis virus (IBV)-induced
injury and reduced the mRNA expression level of IBV in the chicken trachea in vivo. In
particular, the expression of IL-6, TNF-α, and NF-κB was shown to be significantly de-
creased, but mitochondrial antiviral signaling gene, IFN-α, and IFN-β mRNA levels were
shown to be significantly induced in vitro and in vivo [359].
7.4. Other Nutrients and Probiotics

Retinoic acid, an active vitamin A metabolite, was indicated to activate the PI3K/Akt
and NF-κB signaling pathways, leading to proliferation of the cultured chicken primor-
dial germ cells [360]. In LPS-challenged chickens, increased vitamin E supplementation
(50 mg/kg vs. 10 mg/kg) was shown to decrease the expression of nuclear NF-κB p65
and increase the levels of IκBα in the liver [361]. It seems likely that the inhibitory ef-
fects of vitamin E on NF-κB expression could also be seen in physiological conditions,
without any stress challenges. For example, in broilers fed increased vitamin E levels
(14.11–14.91 mg/kg vs. 4.38–4.63 mg/kg) for 21 or 42 days, liver NF-κB p65 levels were
significantly decreased, whereas liver IκB-α levels were significantly increased [362]. The
NF-κB DNA-binding activity in the high-density housing group was shown to increase
significantly compared with the free-range and low-density housing birds. Dietary tau-
rine (0.1%) was shown to significantly alleviate NF-κB DNA-binding activity in chicken
liver [363] and layer oviduct tissue [364], which was initially increased due to high-density
housing systems. Interestingly, in the chicken renal tissue, the same dose of dietary taurine
was able to decrease the NF-κB DNA-binding activity only in the low-density housing
environment [365].
Necrotic enteritis (NE) infection was shown to significantly upregulate the mRNA
levels of the immune-related molecules TLR-2, IL-1β, IL-4, IL-10, IFN-γ, and iNOS and
the growth factors TGF-β3 and insulin-like growth factor 2 (IGF2) in the jejunum of
broiler chickens. However, NF-κB expression was not affected. Interestingly, compared
with nonsupplemented groups, probiotic Enterococcus faecium NCIMB 11,181 was shown
to ameliorate necrotic enteritis-induced intestinal barrier injury in broiler chickens and
increased gene expression levels of TLR2, MyD88, NF-κB, IL-4, iNOS, TGF-β3, PI3K,
IGF-2, glucagon-like peptide-2 (GLP-2), and epidermal growth factor receptor (EGFR).
There was also a significant interactive effect of NE infection and E. faecium treatment on
the mRNA expression of various immune-inflammation factors, including NF-κB [366].
A dendritic cell (DC)-targeted mucosal vaccine using Lactobacillus plantarum as an antigen
delivery system against G57 virus infection was developed. The vaccine was shown to
confer efficient protection against G57 H9N2 infection, due to activation of DCs by the
TLR-induced NF-κB pathway. This was associated with improved DC migration and
improving the presentation of immunogen to T and B lymphocytes, causing changes
in T-cell polarization toward Th1, Th2, and regulatory T cells (Treg cells) and inducing
more efficient mucosal and adaptive immunity responses [367]. Chickens infected with
Salmonella enteritidis (0.5 mL of S. enteritidis bacterial suspension, 109 CFU/mL) through
the oral cavity at 9 days of age) were administered with a probiotic Pediococcus pentosaceus
microcapsule (1 g/kg). It was shown that the probiotic effects on proinflammatory indices
were time-dependent; the probiotic significantly decreased the NF-κB expression in spleen
and cecum samples at 1 dpi, whereas the difference disappeared at 3 dpi, and NF-κB
expression was significantly increased in samples from chickens fed the probiotic at 7 dpi
before disappearing again 14 dpi [368].
8. NF-κB and Inflammation in Poultry Production

Inflammation is known to be a highly orchestrated and tightly controlled protective
mechanism dealing with infection and coordinating the repair and regeneration process.
However, in the case of misregulation of inflammation or its chronic character, it can
be responsible for severe tissue damage [369]. Therefore, elucidation of the molecular
mechanisms underlying the regulation/control and resolution of inflammation is among
the major topics of modern medical and veterinary sciences. Indeed, the relationship
among inflammation, NF-κB signaling, and chronic diseases, including cancer [370], liver
diseases [371], multiple sclerosis [372], immune-related disorders [69,373], and others [374],
has received tremendous attention in recent years. Uncontrolled inflammation is shown
to be associated with many widely occurring human diseases, including cardiovascular
disease, neurodegenerative diseases, diabetes, obesity, asthma, arthritis, and periodontal
diseases [375]. Therefore, modulating inflammation through the negative regulation of
NF-κB signaling is an important approach in medical sciences and clinical practices [376].
In fact, the efficacy, duration, and outcomes of an inflammatory response in poultry
were shown to be condition-dependent and determined by the triggering signal recognized
by the innate immune receptors [377]. It seems likely that poultry metabolic diseases
related to cardiovascular ailments, responsible for a major portion of the flock mortality,
as well as musculoskeletal disorders responsible for slowing down chicken growth and
causing lameness [378] and leg/bone disorders [379], are associated with increased and
misregulated inflammatory responses. Intestinal health is known to depend on a range
of host-related factors (immunity, mucosal barrier), as well as nutritional, microbial, and
environmental challenges. Thus, intestinal dysbiosis, compromised mucosal barrier, and
gut inflammation are among major issues in commercial poultry production systems after
the ban on growth-promoting antimicrobials in animal feed [380]. Furthermore, non-
nutritive dietary ingredients, biosecurity, immunology, vaccine technology, and genetics

are suggested to play an important role in antibiotic-free poultry production [40].
It was hypothesized that subclinical gut disorders leading to a chronic low-level
inflammatory response in the gut associated with oxidative stress and redox disbalance
could result in the disruption of digestive function and poor immune competence [44].
Furthermore, the authors also suggested that chronic intestinal inflammation is responsible
for the decreased performance and increased incidence of intestinal problems observed in
poultry production. In fact, there are a range nutritional stress factors, including feed with
a high content of nonstarch polysaccharides, crude protein excess, ingredient rancidity, or
mycotoxin- and/or heavy-metal-contaminated feed, which could trigger gut inflammation
in poultry species [30,44].
Inflammation and the susceptibility to inflammatory disorders are known to be reg-
ulated by nutrition, the gut microbiome, and genetics. In fact, altered nutrient status is
shown to reprogram host inflammation via the gut microbiota [381]. Furthermore, the
crosstalk between gut bacteria and host immunity is considered to be of great impor-
tance in intestinal inflammation [382], and the intestinal microbiota has emerged as a key
player in metabolic inflammation and dysfunction [383]. The modulation of inflamma-
tory responses associated with NF-κB regulation has been described for many nutrients,
including selenium, taurine, carnitine, silymarin, and other nutrients [30]. Furthermore,
commercially used feed additives, including probiotics, prebiotics, phytobiotics, organic
acids, short- and medium-chain fatty acids, essential oils, and enzymes, can help maintain
optimal host–microbiome interactions to support gut integrity and efficient growth and
health [384,385].
NF-κB is known as a master regulator of the inflammatory response in the complex
inflammatory network, playing a critical role in the host defense against pathogens, and
it protects cells from apoptosis, as a result of triggering the upregulation of proinflam-
matory genes [386]. Furthermore, in acute inflammation, NF-κB, as a redox-sensitive
transcription factor, was shown to participate in condition-dependent selective regula-
tion of the expression of many target genes. They include proinflammatory cytokines
(TNF-α, IL-1β, IL-6, and IL-12), various antioxidants (e.g., glutamate cysteine ligase, SOD1,
SOD2, and catalase) [386], proinflammatory enzymes (secretory phospholipase 2, sPLA2;
COX-2, and iNOS), chemokines (macrophage inflammatory protein 1α (IP-1α), mono-
cyte chemoattractant protein-1 (MCP1), growth factors, cell-cycle regulatory molecules,
anti-inflammatory molecules, and adhesion molecules [387]. Under stress conditions, the
NF-κB network is responsible for balancing the effect of various intracellular stress signals
to maintain homeostasis and cell/tissue integrity [30]. Therefore, a better understand-
ing of the condition-dependent molecular events/mechanisms determining the point at
which NF-κB responses switch from being protective to become damaging is of great
importance [372,388] and awaits further investigation.
9. Conclusions
Today, NF-κB is known as a redox-sensitive, inducible nuclear transcription factor that
regulates the expression of a number of genes associated with important biological pro-
cesses, including innate and adaptive immune responses, cell growth, maturation, survival,
and adaptive homeostasis establishment via interactions with other transcription factors
and vitagenes [1]. Indeed, NF-κB signaling is an important element in cell adaptation to a
diverse array of environmental stimuli, including oxidative stress. These stimuli can be
recognized by various receptors, and the subsequent response involves specific adapter
proteins. Under normal physiological conditions, the antioxidant defense network and
the optimized redox balance in the cell/tissue are responsible for orchestrating important
biological processes associated with cell protection, repair, and growth. This includes
T-cell maturation, fighting against infections, DNA damage repair, and tissue healing and
integrity restoration after injury. However, under various stress conditions, associated with
redox disbalance, aberrant NF-κB activation can lead to detrimental changes, including
the development of many age-related diseases. In fact, it was reported that activation
of NF-κB is an important mechanism of host defense against infection and stress [77].
Indeed, the results from gene knockout experiments clearly showed that mice deficient in
NF-κB-mediated transcriptional regulation were susceptible to a variety of infections and
were characterized by compromised immunity: specifically depressed immunoglobulin
expression, defective humoral immune responses, and decreased responses to LPS [389].
In fact, it was recently proposed that NF-κB is a vital regulator of inflammation, indicating
that the dynamical attributes and the composition of the nuclear NF-κB complexes cumula-
tively instruct context-specific inflammatory gene patterns [48]. A variety of endogenous
and exogenous stimuli in poultry have been characterized, including danger, damage,
and survival signals from viral and bacterial components, proinflammatory cytokines,
DNA damage, growth factors, and other stressors. As mentioned above, the stimuli can
be recognized by a range of various receptors with subsequent activation of NF-κB, along
with involvement of an array of specific adapter proteins [60,67].
Poultry production was shown to be associated with a range of stresses, which can be
divided into four major categories, namely, environmental, technological, nutritional, and
internal/biological stresses [28,29]. It was proven that RONS excess and a compromised
antioxidant defense network are responsible for compromised health, as well as the de-
creased productive and reproductive performance of growing broilers, laying hens and
breeder birds [30,390]. Therefore, the antioxidant defense network in poultry is of great
importance, and understanding the molecular mechanisms underlying its regulation to
optimize redox balance in various tissues and in the body in general under commercially
relevant stress conditions is an important topic of current research in avian biology and
poultry health [26,30].
Our analysis of the recent literature related to the regulatory roles of NF-κB in poultry
can be summarized as follows:
• Similar to mammalian species, in poultry, NF-κB plays a central role in the regulation
of many physiological and pathological processes.
• In thermally stressed birds, NF-κB expression is condition-dependent, including
temperature, exposure duration, and bird’s age.
• The effects of dietary AFB1 on NF-κB expression in chicken liver are also condition-
dependent. In general, AFB1 was shown to compromise AO defenses and increase
proinflammatory cytokine production via NF-κB induction.
• Mn or Cu excess in the chicken diet was shown to increase the expression of NF-κB in
testes, heart, and immune organs.
• The proinflammatory effects of heavy metals (As, Cd and Pb) in chickens were shown
to be mediated via NF-κB pathway activation in various tissues.
• Increased concentrations of NH3 and H2 S (main environmental stressors in poultry
production) in air during chicken housing were shown to impose oxidative stress and
inflammatory responses via NF-κB activation.
• The stimulating effect of LPS on NF-κB expression was shown in vitro in model
systems and in vivo with poultry.
• In many bacterial and viral diseases, NF-κB is activated to increase proinflamma-
tory cytokine production and impose an inflammatory response to create a hostile
environment for pathogens.
• The main bacterial pathogens causing various diseases in poultry production, includ-
ing Escherichia coli, various Salmonella species, Mycoplasma gallisepticum, Eimeria tenella,
Clostridium perfringens, and Chlamydia psittaci, were shown to induce proinflammatory
responses in birds associated with increased NF-κB expression and activity.
• In model systems based on an investigation of gene expression changes due to various
infections, it was proven that the development of viral diseases, including infectious
bursal disease, Newcastle disease, Marek’s disease, and reovirus challenges, was
associated with the induction of NF-κB and inflammatory responses.
• Nutritional modulation of NF-κB expression and activity was shown to be achieved by

using various antioxidants, including selenium, various polyphenols, taurine, retinoic
acid, vitamin E, and some probiotics. In fact, under various stress conditions, these
nutrients can ameliorate (partly or completely) the increased NF-κB expression and
activity imposed by stressors.
An opportunity to use nutritional/pharmacological means to modulate NF-κB ex-
pression and activity should be exploited further to deal with inflammation-associated
poultry disorders/diseases, including gut health problems associated with antibiotic-free
poultry production. In fact, various nutrients, including taurine [391], carnitine [392–394],
silymarin [352], vitamin E [21], selenium [13,20], carotenoids [22], and others [26], have
been shown to affect antioxidant defenses and vitagenes, helping maintain the redox bal-
ance in various chicken tissues. There is a need for further research related to interactions
of the antioxidant defense network with vitagenes and transcription factors, including
NF-κB and Nrf2, which are responsible for the maintenance of redox homeostasis and
stress adaptation under the commercial conditions of poultry production.
Author Contributions: P.F.S. wrote the manuscript; I.I.K. was involved in data analysis; M.T.K. was
involved in data analysis and editing the manuscript. All authors have read and agreed to the
published version of the manuscript.
Funding: P.F.S. and I.I.K. were supported by a grant from the Government of the Russian Federation
(Contract No. 14.W03.31.0013).
Acknowledgments: The authors acknowledge financial support in the form of a grant from the
Government of the Russian Federation (Contract No. 14.W03.31.0013) to P.F.S. and I.I.K.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
AFB1 aflatoxin B1
AKT protein kinase B
ALT alanine aminotransferase
AO antioxidant
AP1 transcription factor
APEC avian pathogenic Escherichia coli
ARD ankyrin repeat domain
ARE antioxidant response element
ATF3 activating transcription factor 3
CAT catalase
COX2 cyclooxygenase-2
CXCLi2 recombinant chicken chemotactic and angiogenic factor 2
Cyt C cytochrome C
DC dendritic cells
dpi days post infection
HDAC3 histone deacetylase3
IBD infectious bursal disease
IBDV infectious bursal disease virus
IFIT5 Interferon-induced protein with tetratricopeptide repeats 5
iNOS inducible nitric oxide synthases
IRF7 interferon regulatory factor 7
LOX5 lipoxygenase 5
NDV Newcastle disease virus
PGC-1α peroxisome proliferator-activated receptor coactivator
p53 tumor protein p53
PPAR peroxisome proliferator-activated receptor
PTEN phosphatase and tensin homolog
PUFAs polyunsaturated fatty acids
ROS reactive oxygen species

RNS reactive nitrogen species
FHS follicle-stimulating hormone
FOXO3 transcription factors
FOXP3 forkhead box protein P3
GCL glutamyl-cysteine ligase
GCLC catalytic subunit of GCL
GR glutathione reductase
Grx glutaredoxin
GSH reduced glutathione
GPx glutathione peroxidase
GST glutathione S-transferase
HAT histone acetyl transferase
HIF hypoxia-inducible factor
HO-1 heme oxygenase 1
HS heat stress
HSP heat-shock protein
IκB inhibitor of κB
IKK IκB kinase
IL-1R IL1 receptor
IFN-γ interferon gamma
Keap1 Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1
LPS lipopolysaccharide
MAPK mitogen-activated protein kinase
MDA malondialdehyde
MIP-1α macrophage inflammatory protein
MG Mycoplasma gallisepticum
MMP16 matrix metalloproteinase 16
Msr methionine sulfoxide reductase
MT3 metallothionein 3
NEMO the regulatory subunit IKKγ
NF-κB nuclear factor-κB
NLR NOD-like receptor
NRLC5 NOD-like receptor family CARD domain containing 5
NQO1 NAD(P)H:quinone dehydrogenase 1
Nrf2 nuclear factor-erythroid-2 (NF-E2) and related factor 2
PCNA proliferating cell nuclear antigen
PGC-1α peroxisome proliferator-activated receptor-gamma coactivator 1α
PPARs peroxisome proliferator-activated receptors
Prx peroxiredoxin
PTGEs prostaglandin E synthase
PGE prostaglandin E
PRR pattern recognition receptor
RANKL receptor activator of NF-κB ligand
RHD Rel homology domain
RONS reactive oxygen and nitrogen species
ROS reactive oxygen species
SeMet selenomethionine
SOD superoxide dismutase
sPLA2 secretory phospholipase 2
STAT3 signal transducer and activator of transcription 3
TGF-β transforming growth factor beta
Th1 T helper cell 1
TLR Toll-like receptor
TNF-α tumor necrosis factor
TNFR TNF receptor
TRAF6 tumor necrosis factor receptor-associated factor 6
TRIF TIR-domain-containing adapter-inducing interferon-β
Trx thioredoxin
TrxR thioredoxin reductase
UCP2 uncoupling protein 2
XOR xanthine oxidoreductase
Wnt4 signaling molecule (Wingless-related MMTV integration site 4)
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antioxidants

Antioxidants 2021, 10, 186. https://doi.org/10.3390/antiox10020186 https://www.mdpi.com/journal/antioxidants

different antibody repertoire, absence of myeloperoxidase in macrophages, etc.) [39–41]

2. Transcription Factor Nuclear Factor Kappa B

cludes a response to genotoxic and oxidative stresses, caused by ultraviolet radiation,

Figure 1. NF-κB target genes (adapted from [65]).

based on T-cell activity is of paramount importance for poultry, including resistance to

Activation of NF-κB and regulation of downstream transcriptional antioxidant

NF-κB is involved in the modulation of many different molecular events, including

of genes responsible for the synthesis of antioxidant or prooxidant molecules, improving

3. NF-κB and Oxidative Stress

Figure 3. Transcription factors andfactors

NF-κB has long been considered to be a prototypical proinflammatory signaling

NF-κB has long been considered to be a prototypical proinflammatory signaling path-

4. Nrf2 and NF-kB Interplay in Oxidative Stress

Table 1. Possible mechanisms of Nrf2–NF-κB interactions.

Mechanisms of Nrf2–NF-κB Interactions References

There is accumulating evidence indicating that various nutrients with antioxidant

Antioxidants 2021, 10, 186 12 of 50

In physiological conditions, a delicate balance between Nrf2 and NF-κB expression

6. Effect of Various Stress Factors on NF-κB Expression and Activity in Poultry

6.3. Mineral Dietary Excess and Heavy-Metal Contamination

6.3.2. As and NF-κB

6.3.3. Cu, As, and NF-κB

of Fabricius of chicken [226]. In the chronic poisoning of Cu and/or As, inflammation

6.3.4. Pb and NF-κB

6.3.5. Cd and NF-κB

6.4. Other Toxic Stress Factors

6.5. LPS-Induced Stress

liver damage as indicated by increased necrotic symptoms, severe fatty degeneration,

6.6.1. Escherichia coli

6.6.3. Mycoplasma gallisepticum

baicalin was reported to restore the mRNA expression of mitochondrial dynamics-related

6.6.4. Eimeria tenella

6.6.5. Clostridium perfringens

6.6.6. Chlamydia psittaci

of Chlamydia psittaci was shown to induce the TLR4/Mal/MyD88/NF-κB signaling axis

6.6.7. Infectious Bursal Disease

6.6.8. Newcastle Disease

6.6.9. Other Viral Diseases

7. Nutritional Modulation of NF-κB in Poultry

were described. Thirdly, in LPS-induced models of oxidative stress and inflammation, Se

7.1.2. Se and Pb Toxicity

7.1.3. Se and Cd Toxicity

proinflammatory effects of Cd dietary supplementation [341]. Similarly, treatment with Se

7.1.4. Se and LPS

7.2. Amino Acids

7.3. Phytogenic Supplements

7.4. Other Nutrients and Probiotics

8. NF-κB and Inflammation in Poultry Production

nutritive dietary ingredients, biosecurity, immunology, vaccine technology, and genetics

• Nutritional modulation of NF-κB expression and activity was shown to be achieved by

ROS reactive oxygen species

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