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Role of interleukin-6 in immunity: A Review

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 ISSN 2348-313X (Print)
International Journal of Life Sciences Research ISSN 2348-3148 (online)
Vol. 4, Issue 2, pp: (268-274), Month: April - June 2016, Available at: www.researchpublish.com

Role of interleukin-6 in immunity: A Review

1
Sana Naseem, 2Dr. Razia Iqbal, 3Talhat munir
1, 3
Student of Mphil zoology, Department Of Zoology University Of Gujrat
2
Associate Professor at UOG, Associate professor of Zoology at University of Gujrat
3
Department of Zoology University of Gujrat Pakistan

Abstract: Itterleukin-6 is a cytokine with an extensive range of biological activities. On the immune system it has
the wide range of impact and it can affect the homeostatic process by having hormone like characteristics. It is
widely used in the clinical intervention because it has both anti and pro-inflammatory properties. It is activated
during inflammation and maturation of B cells. It can act as pyrogen and can cause fever during infection, non-
infection and autoimmune diseases. IL-6 is produced by the macrophages and monocytes in reaction to other
inflammatory cytokines which contain tumor necrosis factor (TNF)-beta and interleukin-11. In resting phase the
receptors of IL-6 is present on normal activated B-cells, cells in hepatic and myeloid cell lines and normal T-
lymphocytes. In the host defense the acute IL-6 expression plays a main role by activates the different cell
population. IL-6 initiates the wide range of acute-phase proteins such as serum amyloid A (SAA), fibrinogen,
hatoglobin, C-reactive protein, hepcidin and antichymotrypsin when acting on hepatocytes and lessend the
cytochrome P450, transferrin, fibronectin and albumin, its structure contains the IL-6R, Sil-6R and gp130.it has
role in many diseases but major role is present in the caner.
Keywords: IL-6, structure of IL-6, signaling of IL-6, role of IL-6 in diseses, IL-6 and cancer.

1. INTRODUCTION

Itterleukin-6 is a cytokine with an extensive range of biological activities. It is mediator for immunoglobulin class
substituting and to regulate the acute phase response. It is also inflammation indicator within body. For the occurrence of
bacteremia IL-6 can also use as investigative marker (Remick, et al., 2005; Fuster, 2014).
IL-6 is an endogenous biochemical which is active during B cell maturation and process of inflammation. It can act as
pyrogen and can cause fever during infection, non-infection and autoimmune diseases (Dalrymple et al., 1996). Either
inflammation chronic or acute it is produced and situation is cancers, trauma, burns and infections (Srirangan & Choy,
2010). IL-6 is also assumed to cause improved susceptibility to systemic form of juvenile rheumatoid arthritis and
diabetes mellitus (Tanaka & Kishimoto, 2012).
IL-6 is produced by the macrophages and monocytes in reaction to other inflammatory cytokines which contain tumor
necrosis factor (TNF)-beta and interleukin-11. In resting phase the receptors of IL-6 is present on normal activated B-
cells, cells in hepatic and myeloid cell lines and normal T-lymphocytes (Kubistova et al., 2012). In B-cells that are
modified by the Epstrin-Barr virus IL-6 is also present. Inflammatory reaction is produced by the IL-6 by initiating the
transcription factors that are present on multiple inflammation pathways. Its origin occurs with protein kinase C,
cAMP/protein kinase A and release of Calcium occurs. IL-6 has various function and forms on the basis of its production
and also has pleiotropic activity (Maeda et al., 2016).
IL-6 is produced by the macrophages and monocytes in the initial stage of infectious inflammation immediately after the
stimulation of Toll-like receptors (TLRs) with separate pathogen related molecular patterns (PAMPs). When
noninfectious inflammation occurs such as traumatic injury or burn then damage related molecular patterns (DAMPs)
from the damages sites activates the TLRs to produce the IL-6 ( Uchiyama et al., 2012) .

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In the host defense the acute IL-6 expression plays a main role by activates the different cell population. IL-6 initiates the
wide range of acute-phase proteins such as serum amyloid A (SAA), fibrinogen, hatoglobin, C-reactive protein, hepcidin
and antichymotrypsin when acting on hepatocytes and lessend the cytochrome P450, transferrin, fibronectin and albumin
(Figure 1) (Wang et al., 2013).
For clinical laboratory tests CRP (C-reactive protein) is a good biomarker of inflammation and its expression is related to
IL-6. If the level of hepcidin that is activated the IL-6 can block iron transporter ferroportin 1 in gut epithelial,
hepatocytes and macrophages it can lead to anemia of chronic inflammation and hypoferremia. TGF- β with the IL-6
enhance the differentiation of IL-17 manufacturing T helper cells that have important role in initiating autoimmune tissue
injury (Eto et al., 2011).
Induction of CD8+ T-cells by the IL-6 is helpful to produce the T cells. Activation of hematopoietic stem cell and
maturation of megakaryocytes into platelets is inducing by the IL-6 in hematopoiesis. Receptor activation of NF-kappa B
ligand is activated by the IL-6 production in bone marrow stromal cells that is important for the activation and
differentiation of bone resorption and osteoporosis (Grossman et al., 1989; Korn et al., 2008). IL-6 in inflamed lesion
such as seen in synovium tissue of rheumatoid arthritis is due to the excessive vascular endothelial growth factor (VEGF)
that increases the angiogenesis. Autoimmune skin disease occurs due to the collagen manufacture in dermal fibroblasts
and also enhanced growth of mesangial cells and plasmacytoma occurs (Laws et al., 2013).

Figure.1: Functions of IL-6

2. STRUCTURE OF IL-6
Signaling of IL-6 is started by relation of IL-6 and IL-6R (IL6RA, CD126) with gp130 dimerization induction and gp130
protein (IL6RB, CD130) that results in a complex of hexameric structure that is capable of signaling. In the body fluids
IL-6R is present in soluble form and it has the ability to bind with IL-6 that leads to trans signaling process of IL-6 so that
expression of gp130 occurs (Simpson et al., 1997; Gruys et al., 2005).
Signaling of IL-6 activates the Ras-Raf, P3K/AKT and JAK/STAT pathways. By activation of different pathways
regulation of pro-tumorigenic and anti-apoptotic activities occur (Escobar‐Morreale et al., 2003). It is most ubiquitously
derestricted cytokine in cancer so it is involve in differentiation and growth of various malignant tumor cells.
Tumorigenesis involve in different tumor models such as lung, ovarian, colon and breast cancer that is due to the
signaling of IL-6-JAK-STAT pathways (Varghese et al., 2002). .

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At the binding line of IL-6-IL-6R-GP130 hexameric complex there are fourteen oncogenic mutations are present that are
mostly related to cancer of colon (7), stomach (1), breast (1), lung (1), endometrial (2) and liver (2) (Guven-Maiorov et
al., 2014).

Figure.2: The structure of IL-6, IL-6RA, and IL-6RB complex (PDB Code_Chains: 1p9m_ABC). Atoms of
interface residues are represented with balls.

3. RECEPTORS AND SIGNALING OF IL-6

Receptors of the IL-6 are including in the family of class I cytokine receptors. In class I receptors greater affinity signal
transduction and ligand binding components are presents. IL-6R has two separate constituents. It has ligand binding
portion which has 80-kDa molecular weight and it is linked to the IL-6 (Mahira et al., 2012; calabrese & Rose-jhon,
2014).
It can be present in two forms such as soluble and membrane bounded form. On the other hand the signal transduction
part of the IL-6R is made up of glycoproteins 130 and can be known as IL-6Rb chain. GP130 has the ability of signal
transduction of IL-6 and establishment of binding site. Gp130 is important molecule in the whole family of IL-6 cytokines
for signaling (Mahira et al., 2012; calabrese & Rose-jhon, 2014).
Circulating complex is formed when the IL-6Ra that is soluble form bind with the IL-6. Now binding of this soluble form
occurs with the cells that will express the gp130 and expression of gene as well as signal transduction occurs. For
mediation of proinflammatory response this complex is very important that lead towards gp130 expression and known as
trans- signaling (Sheller et al., 2011).
Ligand activation of the gp130 takes place by the variety of ways it includes cytoplasmic tyrosine kinases activation and
transcription factor activation. No intrinsic kinase domain is present in the gp130 but various studies reveals that Janus
kinase 1 (JAK1), JAK2 and tyrosine kinase 2(TYK2) of the JAK family are related constitutively with gp130. Signal
transducer and activators of the transcription (STATs) occurs with the help of the kinase activation that is done by the
tyrosine phosphorylation of the latent cytoplasmic transcription factor. STAT3 and Ras protein are activated by the gp130
and IL-6. When activation of Ras protein occur it will lead toward the hypophophorylation of the mitogen-activated
protein kinase (MAPK) and resulted in increased activity of serine/threonine kinase (Ibi & Yamda, 2015).
Phosphorylation of NF-IL6 factor (nuclear factor for IL-6) occurs by the MAPK on threonine 235 and serine 231 that is
important for binding of DNA. In the different acute phase proteins activation occurs with the help of NF-IL6 (Hong et
al., 2007) .

4. ACUTE PHASE RESPONSE OF IL-6

The reaction of an organism to the disturbance due to neoplastic growth, immunological disorder, infection and tissue
injury is involved in acute phase response. It is considered that it is advantageous for the injured organisms to maintain

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the homeostasis after the infection. In acute response IL-1, IL-6 , interferons and IL-6 are involved and these are involve
in various function which include accumulation of clots and platelets, activation of monocytes and granulocytes and blood
vessel leakage (Heinrich et al., 1990)
Innate immune system is enhanced by the IL-6 that activates the acute phase which leads toward protection against
damage of tissue (Kubistova et al., 2012). By the liver cells release of acute phase protein occurs into the plasma of blood,
on the other hand release of other proteins is inhabited. These proteins are very specific in action and mimic the
antibodies. IL-6 enhance the production of two main proteins that are serum amyloid A and C-reactive protein (CRP).
CRP is used to enhance the phagocytic rate of bacteria while SAA is used to alter the gene transcription rate of proteins
(Rincon et al., 2012). Fibrinogen that is essential clotting factor increased by IL-6 while transferrin and albumin level are
diminish at the same time. This lead toward systemic reaction that include enhanced production of glucocorticoids,
complement activation, fever, erythrocyte sedimentation and enhanced clotting (Gruys et al., 2005).

5. ACTION OF IL-6 ON B- AND T-LYMPHOCYTES AND PLASMACYTOMA

IL-6 increase production of immunoglobulin A, G and M by directly activating the B cells and enhance production of IL-
5 and IL-4. It plays important role terminal differentiation of B cells into secretions of immunoglobulin (Shanley et al.,
1996; Wegner et al., 2013). On normal resting B cells IL-6 has no effect because these cells do not show any receptor site
for IL-6 while receptors for IL-6 are shown by the activated B cells and respond to IL-6 antibody secretion and
production. With Epstein-Barr virus, B cells have been pronounced to react to IL-6 with propagation in a paracrine
manner (Wang et al., 2010; Nguyen et al., 2014).
In plasmacytoma (malignant cell tumor within soft tissue or axial exoskeleton) cells function of IL-6 is powerful factor
for growth. IL-3 and IL-6 enhance the differentiation and propagation of precursors of malignant plasma cell in various
myelomas. IL-6 is also important for the proliferation and activation of antigenreceptor dependent T cells. For the
activation of T cells the action of IL-6 is coupled with IL-1. IL-6 initiates the humoral as well as cellular defense
mechanism and monocyte and neutrophil oxidative burst response (Smith et al., 2007).

6. PATHOLOGICAL ROLE OF IL-6 IN DEVELOPMENT OF DISEASES

When synthesis of IL-6 occurs momentarily then it involves in organism defense from environmental stress such as injury
and infection collectively (Dalrymple et al., 1996). It also provides signals for biological events. When stress is
diminished then the production of IL-6 also vanished with the help of negatively regulated system that contain CRP and
serum IL-6 levels (Lopes et al., 2013).
If dysregulation of IL-6 remain continue it will lead toward cancer, different chronic inflammatory and autoimmune
diseases. It was known as all HIV positive patients also contain the Kaposi sarcoma associated herpes virus that persist
the production of IL-6 that is virus derived which activates the gp130 that lead toward disease (Rose-John et al., 2006).

7. ROLE OF IL-6 IN RHEUMATOID ARTHRITIS

Rheumatoid arthritis (RA) is a chronic inflammatory disease that effects the 1% worldwide population of women (Maeda,
206). It includes the inflammation of small joints and synovium that cause the juxta-articular and articular cartilage
destruction that leads toward the osteoporosis, fatigue and anemia (Srirangan & choy, 2010; Ogata et al., 2012).
IL-6 is pleiotropic cytokine which take part in production of auto-antibodies and B-cell maturation which causes the
activation of CRP that plays important role in the pathogenesis of RA (Turiano et al., 2012). IL-6 is involves in the
production of pro-inflammatory lymphocyte that is Th17. It enhance the adaptive immune response, move from acute to
chronic inflammation, development of articular symptoms, enhance joint erosion and enhanced extracellular turn over
(Srirangan & choy, 2010).

8. INTERLEUKIN-6 IN PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE

This disease is divided into two groups such as ulcerative colitis and crohn’s disease. Both of the diseases contain the
relapsing bowel inflammation that reacts to the immunosupresives and glucocorticoids (Saxena et al., 2014). Persistent
inflammation occurs in the sub mucosa and mucosa. Environmental factors as well as various predisposing gene interact
and cause the disease (Turiano et al., 2012).

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IL-6 is function for immune and non-immune system and adaptive and innate immunity. Its production is enhanced by the
activation of cell and it remains normal under control of catacholamines, secondary sex steroids and glucocorticoids. It is
considered that the interaction of complexes and activation of pathways lead toward the Bowl disease (Taka et al., 2012).

9. INTERLEUKIN-6 PROMOTER POLYMORPHISMS (-174 G/C) IN SYSTEMIC LUPUS

ERYTHEMATOSUS
This disease is chronic autoimmune disorder in which inflammation of different organs occurs as well as gathering of
different complexes occur due to B cell hypersensitivity. Mostly the lungs, joints, brain, skin and blood vessels are
affected by this disease (Elnerae et al., 1992). Deposition of immune complexes occurs that destroyed by own body
immune system. Major symptoms are swollen joints, extreme fatigue, rashes and fever and this disease is mostly
occurring in females as compare to males (Maggio et al., 2006).
Both the genetic and environmental factors are involved in initiation of disease. IL-4 preactive B cells are transformed by
the IL-6. It is also involve in the various biological process such as platelet production and metabolism of bone. High
level of mRNA and IL-6 is seen in the patients of SLE (Chua et al., 2009).

10. ROLE OF IL-6 IN SCHIZOPHRENIC PATIENTS

Schizophrenia occurs due to activation of inflammatory system. Involvement of central nervous system occur and IL-6
level in cerebrospinal fluid is important. To know the cause of disease it’s necessary to measure the level of IL-6 and
CSF.IL-6 that is present in the serum is remain high in patients of schizophrenia (Danel & Kaman, 1999; Lopes et al.,
2013)

11. IL-6 AND HYPOPROLIFERATIVE ANEMIA

When IL-6 is combined with cytokines that are proinflammatory then the anemia of inflammation occurs. Modern studies
showed that IL-6 activates the hepatocytes to release the hepcidin. Hepticidin is a used to inhibit the reticuloendothelial
release and intestinal absorption of iron (Kamimura et al., 2014).

12. IL-6 AND CANCER

IL-6 is very important factor for the various types of tumors. There is great relationship between the tumors and the
inflammation (Terzic et al., 2010). Enhanced antiapoptotic, activation of androgen gene receptors and cell cycle gene
expression occurs due to the activation of IL-6 with STAT3 pathways. It has major role in ovarian and prostate cancer.
More production of proinflammatory cytokines important for the cachexia (muscle atrophy, loss of weight and fatigue),
and tumor related symptoms (Sallam et al., 2012).
The role of IL-6 in the angiogenesis, migration, cancer progression and in carcinogenesis is very important. Vascular
endothelial growth factor (VEGF) is important for the angiogenesis that is also enhanced by the IL-6 (Nagasaki et al.,
2014).
The effect of the IL-6 on the cell line of the breast cancer is inhibitory but it has the ability to enhance the metastasis.
2174G/C polymorphism has the ability to promote the phenotype of the breast cancer. When more expression of the IL-6
occurs it will lead towards metastasis and angiogenesis in breast cancer (Hong et al., 2007; Pedersen and Fischer., 2007).

13. CONCLUSION
IL-6 has both pro-inflammatory and anti-inflammatory functions so we can use it for various clinical investigations. It has
role in various diseases but majorly in the cancer. When it’s over production occur different type of cancer occurs it
causes the angiogenesis that lead toward tumor production. So if we control the signaling pathway of the IL-6 we will
control the different type of diseases.

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