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IL-17 Signaling Pathway

Figure 1. IL-17 family signaling pathways

Introduction

Interleukin 17 (IL-17 or IL-17A) is a pro-inflammatory cytokine. This cytokine is generated by a group of T helper cell known as T helper 17 cells. Originally, Th17 was defined in 1993 by Rouvier et al. who isolated IL17 transcripts from rodent T-cell hybridomas. IL-17(A) is a 155-amino acid protein that is a disulfide-linked, homodimeric, secreted glycoprotein with a molecular mass of 35 kDa. Comparison of different members of the IL-17 family uncovers four conserved cysteines that form two disulfide bonds. IL-17 is unique in that it bears no resemblance to other known interleukins. The biologically active IL-17 interacts with type I cell surface receptor IL-17R. After binding to the receptor, IL-17 activates several signaling cascades that, in turn, result in the induction of chemokines. Acting as chemoattractant, these chemokines recruit the immune cells, such as monocytes and neutrophils to the site of inflammation. Typically, signaling events mentioned above follow an invasion of the body by pathogens. Promoting the inflammation, IL-17 acts in concert with tumor necrosis factor and interleukin-1. Moreover, the activation of IL-17 signalling is often observed in the pathogenesis of various autoimmune disorders, such as psoriasis.

The IL-17 family comprises IL17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. IL-17E is otherwise known as IL-25. All members of the IL-17 family have a similar protein structure. According to the test of protein sequences, the researchers found four highly conserved cysteine residues. These conserved cysteine residues are critical to the right 3-dimensional shape of the entire protein molecule. According to previous studies, the members of IL-17 family do not exhibit a significant sequence homology with other cytokines, but the IL-17 family isoforms show a high homology. Moreover, the IL-17 receptor family consists of five, broadly distributed receptors (IL-17RA, B, C, D and E) that present with individual ligand specificity. Within this family of receptors, IL-17RA is the best-described. IL-17RA binds both IL-17A and IL-17F and is expressed in multiple tissues: vascular endothelial cells, peripheral T cells, B cell lineages, fibroblast, lung, myelomonocytic cells, and marrow stromal cells. Signal transduction for both IL-17A and IL-17F requires the presence of a heterodimeric complex consisting of both IL-17RA and IL-17RC and the absence of either receptor results in ineffective signal transduction. This pattern is reciprocated for other members of the IL-17 family such as IL-17E, which requires an IL-17RA-IL-17RB complex (also known as IL-17Rh1, IL-17BR or IL-25R) for effective function. Another member of this receptor family, IL-17RB, binds both IL-17B and IL-17E. Furthermore, it is expressed in the kidney, pancreas, liver, brain, and intestine. IL-17RC is expressed by the prostate, cartilage, kidney, liver, heart, and muscle, and its gene may undergo alternate splicing to produce a soluble receptor in addition to its cell membrane-bound form. In similar manner, the gene for IL-17RD may undergo alternative splicing to yield a soluble receptor. This feature may allow these receptors to inhibit the stimulatory effects of their yet-undefined ligands. The last-described of these receptors, IL-17RE, is known to be expressed in the pancreas, brain, and prostate.

The function of pathway

The gene for human IL-17 is cloned from CD4+ T cells. Each member of the IL-17 family has a distinct pattern of cellular expression. The expression of IL-17A and IL-17F appears to be restricted to a small group of activated T cells, and upregulated during inflammation. IL-17B is expressed in several peripheral tissues and immune tissues. IL-17C is also highly upregulated in inflammatory conditions, and is low in resting conditions. IL-17D is highly expressed in the nervous system and in skeletal muscle and IL-17E is found at low levels in various peripheral tissues.

With the progress of research, much progress has been made in the understanding of the regulation of IL-17. At first, research showed that production of IL-17 is dependent on IL-23. Later, other scientists found that STAT3 and NF-κB signaling pathways are necessary for this IL-23-mediated IL-17 production. Consistent with this finding, another researcher showed that another molecule, SOCS3, plays a major role in IL-17 production. In the absence of SOCS3, IL-23-induced STAT3 phosphorylation is enhanced, and phosphorylated STAT3 binds to the promotor regions of both IL-17A and IL-17F increasing their gene activity. In contrast, some scientists believe IL-17 induction is independent of IL-23. Several labs have identified ways to induce IL-17 production both in vitro and in vivo by distinct cytokines, called TGF-β and IL-6, without the need for IL-23. Despite the fact that IL-23 is not required for IL-17 expression in this situation, IL-23 may play a role in promoting survival and/or proliferation of the IL-17 producing T cells.

Numerous immune regulatory functions have been reported for the IL-17 family of cytokines, presumably due to their induction of many immune signaling molecules. The most notable role of IL-17 is its involvement in inducing and mediating proinflammatory responses. IL-17 is commonly associated with allergic responses. It can induce the production of many other cytokines (such as IL-6, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α), chemokines (including IL-8, GRO-α, and MCP-1), and prostaglandins (e.g., PGE2) from many cell types (fibroblasts, endothelial cells, epithelial cells, keratinocytes, and macrophages). IL-17 acts with IL-22 (produced by T helper 17 cells) to induce expression of antimicrobial peptide by keratinocytes.

The release of cytokines causes many functions, such as airway remodeling, a characteristic of IL-17 responses. The increased expression of chemokines attracts other cells including neutrophils but not eosinophils. IL-17 function is also very important to a subset of CD4+ T-Cells called T helper 17 (Th17) cells. As a consequence of these roles, the IL-17 family has been linked to many immune/autoimmune related diseases including rheumatoid arthritis, asthma, lupus, allograft rejection, anti-tumour immunity and recently psoriasis and multiple sclerosis.

Clinical significance

IL-17 has been strongly associated with pathology, especially in autoimmunity. The efficient IL-17-mediated recruitment of immune cells after bacterial invasion can equally contribute to the initiation of chronic inflammation and autoimmunity. However, IL-17 might not be essential to sustain chronic inflammation. After inflammation has been established, the role of IL-17 may be more limited when the tissues are highly susceptible to immune-cell recruitment. The removal of IL-17-producing lymphocytes and IL-17 protein neutralization with antibodies have had good therapeutic effects in some models, such as psoriasis and rheumatoid arthritis, but not in autoimmune models of multiple sclerosis or inflammatory bowel disease.

IL-17 has a prominent role in rheumatoid arthritis, and high IL-17 expression is noted in the affected joints. The characteristic features of rheumatoid arthritis involve the erosion of cartilage and bone in the affected joints. The resulting joint inflammation leads to enhanced proliferation of synovial fibroblasts, which respond to IL-17 activation similarly to epithelial cells (chemokine, cytokine and MMP production). Main include: the recruitment of immune cells, especially macrophages and neutrophils; and the generation of ectopic GCs. Importantly, neutralizing IL-17 during chronic inflammation disrupts the self-sustaining feedback loop responsible for the recruitment and maintenance of IL-17-producing cells at sites of inflammation. Furthermore, the IL-17-mediated induction of RANKL and recruitment of phagocytic cells markedly increase pathology and result in near-irreversible bone damage. Although this response is highly pathological, it appears to be mediated by the physiological IL-17 program that is usually initiated by a pathogen encounter.

Psoriasis, a chronic inflammation of skin patches that is characterized by epithelial cell hyperproliferation, hyperplasia, immune-cell infiltration and the production of AMPs, is an important example of aberrant IL-17- and IL-22-mediated pathology at epithelia. The synergistic action of IL-17 and IL-22 markedly increases the expression of AMPs, which correlates with disease severity and can be sufficient for the development of psoriasis. The importance and physiological relevance of the induction of AMPs by IL-17 and IL-22 are highlighted by the fact that people with psoriasis are more resistant to skin infections than healthy controls.

Under steady-state conditions, IL-17-producing lymphocytes get rich in the small intestine but not in the colon, and increase in number from proximal to distal small intestine. The colon shows an influx of IL-17-producing cells only after pathogen invasion or if the epithelial barrier is compromised. Reflecting this difference between the small intestine and the colon, dysregulated immunity in the gastrointestinal tract can have a variety of symptoms, as illustrated by the two prototypical inflammatory bowel diseases (IBDs), Crohn’s disease and ulcerative colitis. Interestingly, neutralization of IL-17A has been ineffective in Crohn’s disease. The clinical trial data raise the possibility that the role of IL-17 at the intestinal barrier is different from that in the skin.

In addition, IL-17 plays a multifaceted role in antitumor immunity, and in some aspects even contradicts each other. The number of IL-17-producing cells found in many tumor infiltrates is much greater than that of healthy tissue. Inflammatory signals induced in the tumor environment can instruct cells to secrete IL-17, thus resulting in the subsequent induction of IL-17 targets. At least in part, there is an additive contribution of the local tumor environment to support TH17 cells, as reduced access to metabolites creates conditions in which TH17 cells can thrive. The ability of IL-17 to provide access to tissues and to recruit large numbers of neutrophils has obvious advantages for antitumor responses, because it allows immune cells to gain access to solid tumors. However, the growth of cancers such as melanoma and bladder carcinoma is reduced in IL-17-deficient mice compared with that in IL-17-sufficient controls. It is possible that the IL-17-induced conditions that facilitate the access of immune cells to tumors could also facilitate the migration of tumor cells and their spread via the circulation.

References:

  1. Chiricozzi A., et al. Integrative responses to IL-17 and TNF-α in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. The Journal of Investigative Dermatology. 2011,131 (3): 677–87.
  2. Martin D.A., et al. The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings. The Journal of Investigative Dermatology. 2013, 133 (1): 17–26.
  3. Kolls J.K., Linden A., Interleukin-17 family members and inflammation. Immunity. 2004, 21 (4): 467–76.
  4. Yao Z., et al. Human IL-17: a novel cytokine derived from T cells. Journal of Immunology. 1995, 155 (12): 5483–6.
  5. Aggarwal S., et al. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. The Journal of Biological Chemistry. 2003, 278 (3): 1910–4.
  6. Mangan P.R., et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006, 441 (7090): 231–4.
  7. Ivanov I.I., et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006,126 (6): 1121–1133.
  8. Marc V., Interleukin 17 is a chief orchestrator of immunity. Nature Immunology. 2017, 18: 612-621.
  9. Xu S., Cao X.T.,Interleukin-17 and its expanding biological functions. Cellular & Molecular Immunology. 2010, 7: 164–174.

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