MOLECULAR MEDICINE REPORTS 9: 9-15, 2014

Pathogenesis of endometriosis: The role of initial infection

and subsequent sterile inflammation (Review)
HIROSHI KOBAYASHI, YUMI HIGASHIURA, HIROSHI SHIGETOMI and HIROTAKA KAJIHARA

Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634‑8522, Japan

Received April 5, 2013; Accepted October 14, 2013

DOI: 10.3892/mmr.2013.1755

Abstract. Endometriosis is a common type of chronic 3. Innate immunity and inflammation in endometriosis
inflammatory disease with an immunological background. 4. Role of initial infection
In this review, we aimed to explore the contemporary litera- 5. Role of subsequent sterile inflammation
ture on the infection and sterile inflammation that support 6. Oxidative stress
the pathogenesis of endometriosis. This article reviews the 7. DAMPs
English‑language literature on inflammatory, environmental, 8. Antiapoptosis
immunological and oxidative factors associated with endome- 9. Cytokines
triosis in an effort to identify factors that cause a predisposition 10. Inflammasome
to endometriosis. Intrauterine microbes may be critical for the 11. Novel treatment strategies
initiation of endometriosis; the initial activation of pathogen 12. Antiapoptosis as a target
recognition receptors by microbial stimuli results in the acti- 13. Inhibitors of DAMPs
vation of proinflammatory pathways and innate immunity. In 14. Iron chelators
addition to their response to various exogenous pathogen‑asso- 15. Conclusion
ciated molecular patterns, Toll‑like receptors (TLRs) also
recognize a wide range of endogenous danger‑associated
molecular patterns (DAMPs). The increased expression levels 1. Introduction
of DAMPs may be involved in the subsequent process of
nuclear transcription factor‑κ B‑dependent sterile inflamma- Endometriosis is characterized by the growth of endometrial
tion. Oxidative stress, secondary to the influx of iron during tissue outside the uterus. Endometriosis may result from
retrograde menstruation, is involved in the progression of increased cellular proliferation or a reduction in apoptosis (1).
endometriosis. DAMP‑mediated danger signals and oxidative The balance between proliferation and apoptosis is changed
stress are bidirectional during sterile inflammation (danger in eutopic endometrium from endometriosis. Proposed
signal spiral). This review supports the hypothesis that there hypothetical causes of endometriosis include retrograde
are at least two distinct phases of endometriosis development: menstruation, coelomic metaplasia and embryonic rest.
The initial wave of TLR activation in modulating innate Sampson's theory of retrograde menstruation hypothesizes
immune responses would be followed by the second big wave that the mechanical transfer, invasive implantation and ectopic
of sterile inflammation. growth of endometrial tissues causes endometriosis and it
remains the most widely accepted causal theory. However, no
single theory is able to completely explain the origin and all
Contents aspects of this disorder (2). The mechanisms responsible for
the initial development and subsequent progression of endo-
1. Introduction metriosis are not clear.
2. Study methodology Estrogen is involved in the development and progression
of endometriosis. Treatment for endometriosis is expectant,
medical or surgical. Medical treatment strategies focus on the
creation of states of pseudopregnancy or pseudomenopause.
However, the most crucial problem is that the current medical
Correspondence to: Professor Hiroshi Kobayashi, Department of
and surgical treatments of endometriosis are associated with
Obstetrics and Gynecology, Nara Medical University, 840 Shijo‑cho,
Kashihara, Nara 634‑8522, Japan high rates of relapse. Thus, a novel approach would be a
E‑mail: [email protected] beneficial improvement for the treatment of endometriosis. The
identification of the pathogenesis of this condition is a crucial
Key words: cytokine, endometriosis, sterile inflammation, step for developing novel strategies for the treatment.
oxidative stress, iron, danger signal The present study reviews the contemporary literature on
the infection and sterile inflammation that support the patho-
genesis of endometriosis.
10 KOBAYASHI et al: STERILE INFLAMMATION IN ENDOMETRIOSIS

2. Study methodology Endometriosis is often accompanied by marked changes in

the number and function of inflammatory products, including
The present study reviews the literature for biological studies human neutrophil peptides belonging to the α‑defensin
on the development of endometriosis. Data pertaining to family (11), macrophage migration inhibitory factor (MIF) (12),
in vitro and in vivo studies were included. A computerized C‑C chemokine monocyte chemoattractant protein‑1 (MCP‑1),
literature search was performed to identify relevant studies serum amyloid A (SAA), TNF‑α, IL‑1, IL‑6, IL‑8, chemokine
reported in the English language. All abstracts obtained (C‑C motif) receptor 1 (CCR1) (13) and regulated on activa-
from Medline electronic database were reviewed by two tion, normal T cell expressed and secreted (RANTES) (14).
investigators (Y.H. and H.S.) to identify studies for full‑text Defensin is involved in innate immunity against bacteria
review. The web‑based databases were searched by combining and kills microbes. MIF is a potent proinflammatory and
the keywords ‘TLR’, ‘PAMP’, ‘inflammation’ ‘iron’ ‘oxida- growth‑promoting factor and acts on ectopic endometrial cells
tive stress’ ‘damage’ ‘DAMP’ ‘danger signal’ ‘NF‑κ B’ or to stimulate the production of COX‑2 and PGE2. MCP‑1 acti-
‘antiapoptosis’ with ‘endometriosis’. Additionally, references vates monocytes and recruits into the inflammation site. The
in each report were searched to identify potentially missed hepatic biosynthesis of SAA is upregulated by proinflammatory
studies. Target publications were mainly studies on humans cytokines. CCR1 is a CC chemokine receptor with high affinity
and animal models, as well as basic studies in gene and protein for RANTES. TNF‑α induces the expression of RANTES,
expression systems. Abstracts were not included, as they do which in turn, stimulates recruitment of macrophages into the
not undergo a stringent peer review process. endometriotic tissues. Angiogenic proinflammatory cytokines,
leptin and IL‑8 are potentially involved in the pathophysiology
3. Innate immunity and inflammation in endometriosis of endometriosis (3). Leptin produced by the adipose tissue regu-
lates innate and adaptive immune responses and inflammation.
Endometriosis is associated with angiogenesis, lymphan- IL‑8 has been identified as a chemotactic factor for leukocytes
giogenesis and neurogenesis, which may be induced through and is also produced following inflammation. The levels of
inflammatory cell activation and contribute to the ectopic leptin and IL‑8 are increased in endometriosis, reflecting
growth of endometrial tissue. Mounting evidence suggests inflammation and dysregulated immunomodulation  (3).
that endometriosis is a common type of chronic inflammatory Angiopoietins, ligands of the endothelial TEK (Tie2) tyrosine
disease with an immunological background (3). Substantial kinase receptor, have been associated with angiogenesis (9).
numbers of immune cells, such as macrophages, neutrophils, The Tie2‑expressing macrophages regulate angiogenesis and
dendritic cells, natural killer cells and mast cells, have been lymphangiogenesis to maintain the viability of newly‑formed
identified in peritoneal fluids associated with endometriosis (4) vessels in endometriosis (9).
and macrophage activity may be fundamental in this disorder. These data support the involvement of a chronic inflamma-
However, these immune‑associated cells fail to detect and tory state in endometriotic cells growing in the extra‑uterine
eliminate ectopic endometrial cells, suggesting that they are environment. Cytokines and growth factors may be significant
dysfunctional (4). in endometriosis‑associated inflammation (3,10,15). Principal
The conditions for the development of endometriosis molecular factors of inflammation‑associated angiogenesis,
are induction of angiogenesis and lymphangiogenesis, lymphangiogenesis and neurogenesis should be identified to
which comprise a continuum of vascular development. develop novel therapeutic strategies for this disorder.
Endometriotic lesions, particularly deep infiltrating endome-
triosis, have lymphangiogenic properties. Furthermore, mast 4. Role of initial infection
cells are key mediators of allergic reactions of the immune
system (5) and their immune function may extend far beyond Application of advances in genomic and proteomic tech-
this role  (6). Endometriosis is a common cause of pelvic nologies has provided molecular insights into endometriosis.
pain, possibly by regulating the recruitment of their own Estrogen stimulates proliferation of endometrial and endo-
unique neural supplies through neurogenesis (7). Although metriotic cells. In addition to estrogen, the proliferation of
the precise reason for the endometriosis‑associated increase an endometriotic lesion is regulated by the innate immune
in neurogenesis is unknown, there is evidence of a closer system. Innate immunity is used as a first defense against
proximity between mast cells and nerve fibers, demonstrating pathogens. A microbial infection of the upper genital tract
that mast cells are able to contribute to the development of may be critical for the initiation of chronic pelvic inflamma-
pain (5,8). tion. Although the immune system is able to reject harmful
There is increasing evidence to demonstrate marked eleva- pathogens, commensal microbes have coexisted with cells
tion of proinflammatory cytokines [interleukin (IL)‑1β and at the cell surfaces in a symbiosis (16). Disturbances in the
tumor necrosis factor (TNF)‑α], angiogenic cytokines (leptin maintenance of endometrial homeostasis and regulation of the
and IL‑8), angiogenic growth factors (vascular endothelial host defense against bacterial infection lead to a break in the
growth factor and protein kinase CK2) and prostaglandin endometrial barrier function in genetically‑susceptible hosts.
concentrations in endometriosis (3,7,9). IL‑1β and TNF‑α in Spontaneous contamination of Escherichia coli in menstrual
peritoneal fluid are able to activate c‑Jun N‑terminal kinase blood and peritoneal fluid may promote Toll‑like receptor
(JNK) in eutopic endometrial cells from women with endome- (TLR) 4‑mediated growth of endometrial tissue originating
triosis, which in turn may upregulate inflammatory cytokine from retrograde menstruation (17). The TLR system responds
expression (10). JNK is also activated in response to cellular immediately to infectious agents. The proinflammatory
stress (10). innate immune response leads to the activation of the slower
 MOLECULAR MEDICINE REPORTS 9: 9-15, 2014 11

adaptive immune system. It has also been reported that the At least two waves of inflammation‑induced gene expres-
TLR4  A896G polymorphism (rs4986790) is a functional sion occurs in endometriotic tissues. The first wave includes
polymorphism resulting in peritoneal inflammation  (18). conserved infection and immune‑associated early genes. The
The initial development of endometriosis, e.g., adhesion and second‑wave genes encode oxidative stress and sterile inflam-
growth of ectopic endometrial tissue, may be characteristically matory factors required for proper regeneration. Therefore, the
non‑sterile (Fig. 1, Step 1). initial wave of the LPS‑dependent TLR activation in modu-
Host pathogen recognition receptors (PRRs) recognize lating immune responses would be followed by a second wave
microbial structures referred to as pathogen‑associated molec- of the mechanisms responsible for enhancing the oxidative
ular patterns (PAMPs) (16). TLRs are the first class of cell stress and sterile inflammation.
PRRs (16,19). These PAMPs include lipopolysaccharide (LPS)
and other components such as flagellin, a bioactive TLR5 6. Oxidative stress
ligand  (16). PAMPs trigger intracellular signaling events,
including ion influxes, cytosolic Ca2+ accumulation, produc- Although the mechanism by which oxidative stress induces
tion of reactive oxygen species (ROS) and phosphorylation of inflammation remains unclear, one prominent and early medi-
specific proteins, and their signaling pathways are involved ator for inflammation in endometriosis may be free iron (21).
in innate immunity through activation of TLRs. TLR activa- Redox active metals such as iron possess the ability to produce
tion induces key inflammatory mechanisms such as nuclear reactive radicals, for example the superoxide anion radical.
transcription factor‑κ B (NF‑κ B) activation and the synthesis Iron‑induced inflammation is mediated through ROS produc-
of IL‑1β mRNA  (19). A complex network of pathways is tion by driving the Fenton reaction (Fig. 1, Step 2). Excessive
targeted by immunosuppressive cytokines such as IL‑10 and production of ROS is secondary to peritoneal influx of
transforming growth factor (TGF)‑β. pro‑oxidants such as iron during retrograde menstruation (22).
TLR‑mediated inflammation possibly occurs through the Iron is able to induce oxidative stress in endometriosis during
exogenous PAMPs as well as the endogenous danger‑asso- the secondary persistent inflammatory response (23). ROS
ciated molecular pattern (DAMP) ligands  (2). Nucleotide induce cellular and DNA damage and increased proinflamma-
oligomerization domain‑like receptors (NLRs) and, to a lesser tory gene expression through NF‑κ B activation (22). In mice
degree, the retinoic acid‑inducible gene I‑like receptors are deficient for the NF‑κ B family, endometriosis development
intracellular sensors  (16). Activation of PRR signaling via was reduced (24). Iron also induces IL‑1β expression, and the
members of the TLR and NLRs families initiates inflam- inhibition of IL‑1β prevents development of endometriosis.
matory defense mechanisms that are required to protect the These data allow us to hypothesize that the iron overload
host. NLRs respond to a variety of pathogen and intracellular affects numerous mechanisms involved in the development of
danger signals (20) and induce the transcription of proinflam- endometriosis during sterile inflammation. Iron and NF‑κ B
matory cytokines via the activation of NF‑κ B (19). NLRC5, appear to be connected, making these signaling pathways an
expressed through the signal transducers and activators of the attractive target for the future treatment of this disease (23).
transcription 1‑mediated signaling pathway, has been identified Sterile inflammation and oxidative stress by redox‑active iron
as a regulator of NF‑κ B, type I interferon (IFN) and inflam- may lead to a circulus vitiosus, resulting in the persistence of
masome signaling pathways (see section 10) (20). NLRs also inflammatory processes and the development of endometriosis
trigger mitogen‑activated protein kinase signaling pathways when the process becomes chronic (2).
and control the activation of inflammatory caspases and subse-
quent activation of proinflammatory cytokines (16). Activation 7. DAMPs
of caspase‑1 is essential for the processing of pro‑IL‑1β and
pro‑IL‑18 (16). In the absence of the anti‑inflammatory feed- TLRs are a critical environmental interface that regulate
back signals, physiological defense mechanisms may turn into infection and sterile injury by responding to a variety of
pathological responses. microbial and endogenous ligands (25). In addition to their
Gene expression profiling studies may reveal factors that response to various exogenous PAMPs, TLRs recognize a
explain variability in the development and progression of wide range of endogenous DAMPs, including high‑mobility
endometriosis. Notably, TLR activation in eutopic endome- group box protein 1 (HMGB1), heat shock protein 70 (HSP70),
trium may be involved in the initial inflammatory response. adenosine‑5'‑triphosphate (ATP), DNA, urate crystals,
The increased expression levels of several factors, including asbestos, silica, aluminum hydroxide, S100, neutrophil elas-
inflammatory cytokines and innate immunity, may be involved tase, amyloid‑β and soluble extracellular matrix components,
in the process of TLR‑dependent inflammation (2). Khan et al such as biglycan, hyaluronan, versican, fibrinogen, heparan
studied the role of bacterial LPS and TLR4 in endometriosis, sulfate fragments and fibronectin extra domain A (2,26,27).
suggesting the association between bacterial infection and Intracellular contents released from damaged cells into the
endometriotic proliferation (17). Bacterial LPS may have an extracellular space serve as DAMPs or alarmins that trigger
initial role in the development of endometriosis. inflammation (Fig. 1, Step 3). Infection and damage cause
inflammation as PAMPs as well as DAMPs are immunogenic.
5. Role of subsequent sterile inflammation There is increasing evidence that this sterile inflammatory
response mediated through DAMPs is a key determinant of
Inflammation is part of the non‑specific immune response. In further development of inflammation‑associated diseases
certain cases, the inflammatory process becomes continuous such as atherosclerosis, gout, type II diabetes and pancre-
and the early endometriotic lesion may develop subsequently. atitis (26). A number of DAMPS, including HMGB1, DNA,
12 KOBAYASHI et al: STERILE INFLAMMATION IN ENDOMETRIOSIS

ATP and HSP70, have been shown to be involved in endo- triosis. These findings require additional preclinical studies on
metriosis (2). The TLR‑mediated inflammation persistently DAMPs in endometriosis.
occurs possibly through the endogenous ligands. Persistent
sterile inflammatory insults and DAMPs released from 8. Antiapoptosis
damaged cells are bidirectional, and they activate immunity
and further propagate tissue damage. Specific DAMP recep- The release of DAMPs from endometriotic‑damaged cells
tors, including TLR4, TLR9 and P2X7, as well as downstream may engender a second wave of tissue damage during acute
DAMP‑sensing components, including NLRP3, caspase‑1, processes and, if chronic, potentially trigger antiapoptotic
IL‑1β, IL‑18 and IL‑1 receptor, are required for full experi- processes. Increased levels of cell proliferation and reduced
mental endometriosis (26). These DAMP‑mediated pathways levels of apoptosis emerge as major mechanisms responsible
may provide novel therapeutic targets. for the development of endometriosis. Attenuated susceptibility
Mesothelial cells undergo injury and repair themselves to apoptosis may contribute to the pathogenesis of endome-
following retrograde menstruation‑associated inflammation. triosis (31,32). Marked cell proliferation has been attributed
Peritoneal endometriosis is the result of ectopic implantation and to a change in the expression levels of proteins such as B‑cell
growth of endometrial tissue in women with a deficient immune lymphoma‑2 (Bcl‑2) and Bcl‑2‑associated X proteins (Bcl‑XL,
system, which is not able to defend against regurgitated endome- Bcl‑XS). A number of other genes are associated with apop-
trial cells (28). Specific factors, including TNF‑α, α‑enolase and tosis in endometriosis, including defender against cell death‑1,
hemoglobin, in menstrual effluent induce epithelial to mesen- P53, survivin, caspase‑1, calpain, proliferating cell nuclear
chymal transitions (EMT) in mesothelial cells, resulting in cell antigen and PGE2 synthesis genes (31,33‑35). PGE2 promotes
retraction and exposure of the submesothelial extracellular cell survival through the EP2/EP4 receptor‑dependent
matrix (ECM) (28). Structural damage of the mesothelial layer activation of ERK1/2, Akt, NF‑κ B, and β‑catenin signaling
attributable to the menstrual effluent may facilitate regurgitated pathways, suppressing proapoptotic proteins (Bax and Bad)
endometriotic cell adhesion and growth. Fibrosis around the and enhancing antiapoptotic proteins (Bcl‑2/Bcl‑XL) (33). The
endometriotic foci is the consequence of recurrent cell damage. PGE2 signaling components are abundantly expressed in endo-
Endometriotic cell migration and the concomitant degradation metriosis (33). COX‑2 induces PGE2 expression through the
of ECM are two essential steps in the invasive process. ECM cAMP/ERK pathways by activating EP2 and EP4 receptors.
components such as biglycan, hyaluronan, versican, fibrinogen, COX‑2 also reduces apoptosis‑associated caspase‑3 expres-
heparan sulfate fragments and fibronectin extra domain A have sion (36). Selective COX‑2 inhibition induces regression of
now been demonstrated to act as signaling molecules (29). They endometrial grafts by stimulation of apoptosis (36). Decreased
act as fundamental danger signals or DAMPs, signifying tissue apoptosis is also associated with a pathway involving
injury, and they also potentiate the immune system (29). The HOXA10, calpain5 and caspase  (37). Expression levels of
expression of certain danger signal proteins involved in the calpain5, a target of HOXA10 transcriptional regulation, are
organization of the cytoskeleton, signal transduction, regulation reduced in endometriosis which is likely to be the result of
of the redox state and production of ATP, has been demonstrated reduced HOXA10 expression levels (37).
to be altered during the EMT process.
ATP is a ubiquitous molecule in every cell and is released into 9. Cytokines
the extracellular milieu following tissue injury. Extracellular
ATP is a host‑derived small‑danger‑molecule. ATP synthase Commonly upregulated cytokines in endometriosis include
β subunit has been demonstrated to be differentially expressed IL‑1β, TNF‑ α, IFN‑γ, IL‑18, IL‑10 and TGF‑ β. IL‑1β and
between women with and without endometriosis. ATP synthase IL‑18 are two powerful proinflammatory cytokines with pleio-
β‑chain has been identified as phosphorylated and activated in tropic activities. IL‑18 increases natural killer cell activity, and
endometriosis. Thus, extracellular ATP released from ectopic stimulates IFN‑γ production in T‑helper type I cells. IL‑18 is
endometrial cells may constitute a major endogenous danger involved in various immune diseases and induces COX‑2 in
signal that leads to IL‑1β expression and fibrosis. peritoneal monocytes (38). Although there are a number of
Although DAMPs such as endogenous DNA and nuclear studies on the association between IL‑18 and endometriosis,
HMGB1 have been shown to be critical in sterile inflam- their results appear to be contradictory (38).
mation, the role of nuclear histone proteins has not yet been Upregulation of IL‑10 expression levels was also observed
investigated in endometriosis. Numerous studies (26) have in ovarian endometrioma when compared with a control
established that certain non‑histone proteins such as HMGB1 group  (39). The biological actions of IL‑10 are inhibitory,
are released extracellularly and induce innate/inflammatory including the inactivation of macrophages and inhibition of
and adaptive immune responses as a DAMP. DNA binds proinflammatory cytokines, demonstrating that IL‑10 func-
histones to form nucleosomes. Ischemia/reperfusion (I/R) tions as an immunoregulatory cytokine.
injury of several organs enhances histone expression and Host‑derived TGF‑β1 is a multifunctional cytokine that is
selected proinflammatory/profibrotic genes. Injection of upregulated in endometriosis (40). TGF‑β1 induces the secre-
exogenous histones exacerbates injury through the TLR9 and tion of IL‑6 from endometrial stromal cells through an increase
MyD88‑mediated cytotoxic effects, and histone neutralization in protease‑activated receptor (PAR)‑2 expression levels (41).
protects against injury (30). Histones function as a DAMP TGF‑β1 may enhance the development of endometriosis (40).
following I/R injury (30). We hypothesize that histones may NF‑κ B is involved in the transduction of proinflammatory
be a novel class of DAMP molecules and serve as an activator signals, upregulation of adhesion molecules and suppression of
of innate immunity during sterile inflammation in endome- apoptosis, thus enhancing the initial development of endome-
 MOLECULAR MEDICINE REPORTS 9: 9-15, 2014 13

Figure 1. Initial infection and subsequent sterile inflammation are essential for the development and progression of endometriosis. (Step 1) Spontaneous
contamination of Escherichia coli in menstrual blood may promote TLR‑mediated growth of endometrial tissue originating from retrograde menstruation.
TLRs recognize microbial structures referred to as PAMPs. TLR activation is involved in the initial inflammatory response and innate immunity.
(Step 2) Excessive production of ROS through the Fenton reaction is secondary to the peritoneal influx of free iron during retrograde menstruation.
(Step 3) ROS induce cell and DNA damage and increased proinflammatory gene expression through the DAMP‑mediated NF‑κ B activation. Therefore, the
initial wave of the LPS‑dependent TLR activation in modulating immune responses would be followed by a second wave of the mechanisms responsible
for enhancing the oxidative stress and sterile inflammation. TLR, toll‑like receptor; PAMPs, pathogen‑associated molecular patterns; ROS, reactive oxygen
species; DAMP, danger‑associated molecular pattern; NF‑κ B, nuclear transcription factor‑κ B; LPS, lipopolysaccharide.

triosis (43). NF‑κ B, as a series of cascade events of an autocrine inflammation and oxidative stress should be developed. Novel
nature, regulates the expression of proinflammatory cytokines treatments from genomic investigations may be identified
and activation of NF‑κ B itself, leading to the maintenance of due to the accumulation of a therapeutic signature for endo-
autocrine self‑amplifying cycles (Fig. 1). metriosis. A high‑throughput screening assay is capable of
revealing a number of compounds that specifically inhibit a
10. Inflammasome target molecule activity.

Production of pro‑IL‑1β, an inactive precursor, is induced by 12. Antiapoptosis as a target

the activation of NF‑κ B in response to inflammatory stimuli.
In the generation of IL‑1β, additional proteolytic cleavage Antiapoptosis may be involved in the pathophysiology of
by cytosolic protein complexes termed ‘inflammasomes’ is endometriosis  (32). Accordingly, apoptosis of the nascent
required for the activation of pro‑IL‑1β (16). Inflammasomes endometriotic lesion has become an attractive target to
assemble in response to endogenous danger signals. Caspase‑1 use to inhibit the development of endometriosis. An array
is auto‑activated within inflammasomes that include NLR of promising therapeutic agents, including BAY  11‑7085,
proteins, the adapter apoptosis‑associated speck‑like protein β ‑hydroxyisovalerylshikonin ( β ‑HIVS), bufalin and
containing a C‑terminal caspase recruitment domain and rapamycin, have entered various stages of preclinical devel-
pro‑caspase‑1  (16). Accumulating evidence indicates that opment for endometriosis. Bay 11‑7085 is reported to inhibit
several sterile inflammatory responses triggered by oxida- NF‑κ B activation and this pharmacological inhibitor induces
tive stress or cell damage are mediated by inflammasomes. apoptosis through the suppression of antiapoptotic proteins
Subsequent activation of inflammasomes leads to NF‑κ B such as caspase‑3,  ‑8, and  ‑9  (43). Extract of the roots of
activation and IL‑1β production, resulting in inflammatory Onosma paniculata, β ‑HIVS, induces apoptosis in cancer
responses. Therefore, we hypothesize that the inflammasome is cells (44). β ‑HIVS is an ATP non‑competitive inhibitor of
an initial sensor for danger signals in endometriosis. However, protein‑tyrosine kinases. It induces G0/G1 phase cell‑cycle
regulation of the inflammasome formation in endometriosis is arrest and apoptosis via the downregulation of Bcl‑2 expres-
poorly understood. sion with the activation of caspase‑3, ‑8 and ‑9, leading to the
inhibition of endometriotic cell proliferation (44). Bufalin, an
11. Novel treatment strategies apoptosis‑inducing agent, is a major digoxin‑like compound
isolated from the skin and parotid venom glands of toads (35).
This review allows us to hypothesize that several promi­ Rapamycin is a drug with antifungal, immunosuppressant,
sing therapies that target DAMPs in antiapoptosis, sterile antiapoptotic and antiangiogenic effects (45). The apoptotic
14 KOBAYASHI et al: STERILE INFLAMMATION IN ENDOMETRIOSIS

activities of these agents may be sufficient for additional release of DAMPs from damaged cells may engender a second
clinical investigation on the development of endometriosis. big wave of tissue damage during chronic processes and
potentially trigger sterile inflammation‑induced antiapoptotic
13. Inhibitors of DAMPs and oxidative stress processes. In conclusion, initial infection
and subsequent sterile inflammation are closely associated
Molecules of DAMPs are stimulated under conditions of stress, with the development of endometriosis.
such as injury, infection, ischemia or oxidative stress. They
induce immune tolerance or various chronic diseases such Acknowledgements
as arthritis, atherosclerosis, cancer, systemic lupus erythema-
tosus and possibly endometriosis. These data suggest a role This study was supported by a Grant‑in‑Aid for Scientific
for DAMP molecules in the enhanced and persistent activation Research to H.K. from the Ministry of Education, Culture,
of endometriosis. HMGB1 functions as a major DAMP and Sports, Science and Technology (Tokyo, Japan).
inhibits apoptosis, promoting Bcl‑2 expression and inhibiting
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