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IL-17 Family

Overview

Interleukin-17 (IL-17) is a pro-inflammatory cytokine secreted by activated T-cells. Recently discovered related molecules are forming a family of cytokines, the IL-17 family. The prototype member of the family has been designated IL-17A. Recent advances in the human genome sequencing and proteomics five additional members have been identified and cloned: IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. The cognate receptors for the IL-17 family identified thus far are: IL-17R, IL-17RH1, IL-17RL (receptor like), IL-17RD and IL-17RE. However, the ligand specificities of many of these receptors have not been established. The IL-17 signaling system is operative in disparate tissues such as articular cartilage, bone, meniscus, brain, hematopoietic tissue, kidney, lung, skin and intestine. Thus, the evolving IL-17 family of ligands and receptors may play an important role in the homeostasis of tissues in health and disease beyond the immune system.

Figure 1. Diversity of cytokine-receptor interactions.

Members of IL-17 family

Table 1. IL-17 family related products

IL-17 Family Ligands

IL17 IL17A IL17B
IL17C IL17D IL17E / IL25
IL17F

IL-17 Family Receptors

IL17RA IL17RB IL17RC
IL17RD IL17RE
  • IL-17A and IL-17F

Interleukin-17 (IL-17A) is a cytokine secreted exclusively by activated T-cells. IL-17 cDNA has been isolated and cloned from the murine hybridomas (cytotoxic T lymphocyte antigen 8 (CTLA-8)) and has homology to open reading frame 13 from the T lymphotropic Herpesvirus saimiri. The human IL-17A gene product is a protein of 150 amino acids with a molecular weight of 15 kDa, and is secreted as a disulfide linked homodimer of 30–35 kDa glycoprotein. This cytokine regulates the activities of NF-kappaB and mitogen-activated protein kinases. This cytokine can stimulate the expression of IL6 and cyclooxygenase-2 (PTGS2/COX-2), as well as enhancing the production of nitric oxide (NO).

In humans, IL-17A activity can be inhibited by soluble IL- 17RA and IL-17F inhibited by IL-17RC, respectively, whereas soluble IL-17RA/IL-17RC heterodimeric receptors are required to inhibit IL-17F/IL-17A activity. Furthermore, the distribution of IL-17RA and IL-17RC in tissues seems to be different. IL-17RA mRNA highly expresses in T cells and lymphoid tissues, while IL-17RC mRNA expresses in non-hematopoietic tissues such as the colon, small intestine, and lung. In addition, the existence of several isoforms of these receptors suggests a large number of splicing variants. Thus, the differential expression and their alternative splicing forms of IL-17 receptors may contribute to different roles of IL-17A and IL- 17F. Early studies showed that IL-17A and IL-17F induced inflammatory cytokines in mouse embryonic fibroblasts (MEFs) through the activation of NF-κB and mitogen-activated protein (MAP) kinase pathways.

Homodimers of IL-17A, IL-17F and IL-17A/F heterodimer signal through a heterodimeric complex of IL- 17RA and IL-17RC. Lack of either IL-17RA or IL-17RC completely abrogates the inflammatory function of IL-17A and IL-17F. However IL-17A and IL-17F have a biased binding affinity for the hetero-receptor. IL-17A binds better to IL-17RA than IL-17RC and IL-17F binds to IL-17RC with an ~10-fold higher affinity than to IL-17RA, while IL-17F/IL-17A hetero- dimer binds with a similar affinity to both receptors. In addition, IL-17RA binds to IL-17A with an affinity about 100- fold higher than its affinity for IL-17F.

  • IL-17B, IL-17C and IL-17D

IL-17C is mainly produced by epithelial cells and was recently found to be important in promoting cytokines and anti-microbial peptides production in the gastrointestinal tract. Similar to IL-17A, IL-17C is implicated in protection against microbial infection as well as in the pathogenesis of autoimmune disease including psoriasis and multiple sclerosis. IL-17C signals through the IL-17RA/IL-17RE receptor complex and Act1 to pro-mote innate host defense and regulate the intestinal inflammation and barrier function. IL-17RE is upregulated on Th17 cells upon differentiation and has been shown to promote Th17 differentiation through the induction of NFκBIZ. Mice lacking IL-17C are partially resistant to EAE. NFκB and MAPK path-ways were activated by IL-17C in colon epithelial cells but not in IL-17RE deficient cells. IL-17C was demonstrated to be important for early mucosal responses to C. rodentium infection. IL-17C was substantially induced in colon epithelial cells as early as day 4 post C. rodentium challenge and synergized with IL-22 for anti-microbial peptides production. In the absence of its functional receptor, IL-17RE, mice exhibited impaired anti-microbial peptide, cytokine and chemokine production during C. rodentium infection and succumbed to infection within 13 days.

IL-17B was detected in several organs with high expression in chondrocytes and neurons. IL-17B was reported to bind to IL-17RB, though with lower affinity than IL-25 and stimulated the production of TNF-a and IL-1b by the monocytic cell line, THP-1. Furthermore, it was highly expressed in the cartilage derived from the paws of collagen-induced arthritis mice, suggesting a potential pro-inflammatory role in disease processes. IL-17D was also detected in several organs, whereas in immune cells, IL-17D is only expressed in resting CD4+ T cell and CD19+ B cells. The biological function of IL-17B and IL-17D are still poorly understood. The receptor for IL-17D has yet to be solved.

  • IL-17E (IL-25)

IL-25 is a distinct cytokine in the IL-17 family originally identified by sequence homology search and its expression was first characterized in highly polarized Th2 cells, implicating its role in type-2 immune responses. Latter studies have suggested that IL-25 also expresses in mast cells upon IgE cross-linkage, in alveolar macrophages, eosinophils and basophils. We and others also found that IL-25 mRNA expresses in lung epithelial cells treated with allergen or intestinal epithelial cells exposed to commensal bacteria. Indeed, airway epithelial MMP7 can modulate IL-25 activities in the airway during allergic asthma. Furthermore, IL-25 is constitutively expressed in brain microglia and brain capillary endothelial cells to control local inflammation in the brain and maintain blood brain barrier integrity. These data indicates that there might be several potential IL-25 producers in vivo. Although data so far suggests the importance of IL-25 in type-2 immunity, the downstream signaling pathway regulating IL-25 expression and function has not yet been clarified.

Figure 2. IL-17F structure comparison among the known structures of the cysteine knot fold family.

Cellular functions

IL-17 and IL-17F are associated with several immune regulatory functions. Most notably, they are involved in the inflammatory process during infection and in the pathogenesis of chronic inflammation in autoimmune diseases. Fibroblasts, epithelial cells and macrophages are known targets for IL-17A in inducing the expression of many proinflammatory cytokines and chemokines, including CXCL1 (Gro1), CCL2, CCL7, CCL20, and matrix metallopro-teinase (MMP) 3 and 13. As a result, IL-17A mediates the recruitment of neutrophils and macrophages during inflammation. IL-17A blockade leads to reduced severity of experimental autoimmune encephalomyelitis (EAE), while overexpression of IL-17A in lung epithelial cells causes airway inflammation. Because IL-17A and IL-17F share the highest homology, there is a considerable overlap in their biologic functions. Although less active than IL-17A, IL-17F also has an ability to induce the production of antimicrobial peptides (defensins), cytokines (IL-6, G-CSF, and GM-CSF), chemokines (CXCL1, CXCL2, and CXCL5), as well as enhance granulopoiesis and neutrophil recruitment. Over- expression of IL-17F in the lungs resulted in increased proinflammatory cytokine and chemokine expression, airway inflammation predominantly infiltrated with neutrophils and macrophages.

IL-17C directly promotes the expression of the tight junction molecule occludin by colonic epithelial cells, suggesting the critical role of IL-17C in maintaining intestinal barrier function. Fur-thermore, IL-17C is also involved in skin inflammation. Deficiency of IL-17C leads to attenuated imiquimod-induced skin inflammation, while over-expression of IL-17C in keratinocytes leads to spon-taneous psoriasiform skin inflammation in mice.

A study in renal carcinoma cell lines shows that IL-25 induces the expression of proinflammatory cytokine, IL-8, through NF-κB activation. However, studies in vivo indicate that the major biologic function of IL-25 is involved in type-2 immune response. The receptor for IL-25 appears to be the same as the receptor for IL-17B (EVI27) but with a higher binding affinity. Recent finding indicates that the functional IL-25 receptor indeed needs not only IL-17RB but also IL-17RA, because mice deficient of IL-17RA or IL-17RB do not respond to IL-25. Intriguingly, we analyzed the mRNA expression of IL-17RB in helper T cell subsets and found that in vitro generated Th2 cells but not Th1 cells expressed IL-17RB, indicating its function in the regulation of helper T cell development. By using anti-IL-17RB receptor antibody, we show the surface IL-17RB expression in Th2 cells. These data indicates that there might be several cell types contributing to the function of IL-25 in regulating type-2 immune response. Depending on the disease models and timing of analysis, different IL-25 responding cells may appear and participate in promoting type-2 immune responses.

Role in disease

Interleukin-17 cytokines have been studied in a variety of other tissues and diseases. A large body of evidence shows that IL-17A and IL-17F (ML-1) are involved in asthma. Asthma is marked by the recruitment of neutrophilic leuko-cytes into the airway, a process thought to be regulated by T-cells through pro-inflammatory cytokines such as IL-6 and TNF-α. IL-17A and IL-17F expression are increased in asth-matic versus normal patients, and both cytokines have been shown to induce IL-6 and IL-8 expression.

IL-17C has also been shown to have a protective role in intestinal inflammation as mice lacking IL-17C exhibit exacerbated DSS-induced colitis.

In humans, IL-25 mRNA is highly expressed in autoimmune uveitis diseases. Furthermore, IL-25 therapy results in a T cell-mediated dominant protective effect against autoimmune diabetes in NOD mice. Further studies on the roles of IL-25 will provide better understanding of IL-25 function in autoimmune diseases. In addition, IL-25 has potent antitumor activity in vivo in several human cancers including melanoma, breast, lung, colon, and pancreatic cancers, suggesting the potential clinical use of IL-17E as an anticancer agent.

References:

  1. Moseley TA, Haudenschild DR, Rose L. "Interleukin-17 family and IL-17 receptors". Cytokine Growth Factor Rev. 2003, 14 (2): 155–74.
  2. Johansen C, Usher PA, Kjellerup RB. "Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin". Br. J. Dermatol. 2009, 160 (2): 319–24.
  3. Aggarwal, S, Ghilardi, N, Xie, M.H. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 2003, 278, 1910–1914.
  4. Ely, L.K., Fischer, S., and Garcia, K.C. Structural basis of receptor sharing by interleukin 17 cytokines. Nat Immunol 2009, 10, 1245–1251.
  5. Lee J, Ho WH, Maruoka M. "IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1". The Journal of Biological Chemistry. 2001, 276 (2): 1660–4.
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