Interleukin 17

The IL-17 family in humans comprises IL17A (sometimes confusingly called "IL-17"), IL17B, IL17C, IL17D, IL17E and IL17F. IL-17E is also known as IL-25. All members of the IL-17 family have a similar protein structure. Their protein sequences contain four highly conserved cysteine residues. These conserved cysteine residues are critical to the right 3-dimensional shape of the entire protein molecule. To the reference, the members of the IL-17 family do not exhibit a significant sequence homology with other cytokines. Among IL-17 family members, the IL-17F isoforms 1 and 2 (ML-1) have the highest sequence homology with IL-17A (55 and 40%, respectively). They are followed by IL-17B, which has 29% similarity to IL-17A, IL-17D (25%), IL-17C (23%), and IL-17E (17%). In mammals, the sequences of these cytokines are highly conserved. For instance, the sequence homology between the corresponding human and mouse proteins is usually between 62–88%.{{cite journal | vauthors = Kolls JK, Lindén A | title = Interleukin-17 family members and inflammation | journal = Immunity | volume = 21 | issue = 4 | pages = 467–76 | date = October 2004 | pmid = 15485625 | doi = 10.1016/j.immuni.2004.08.018 | doi-access = free }}

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. IL-17 induces 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 mainly by T helper 22 cells in humans, but by T helper 17 cell in mice) 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 essential to a subset of CD4+ T-Cells called T helper 17 (T_h17) cells. As a result of these roles, the IL-17 family has been linked to many immune-related/autoimmune diseases including rheumatoid arthritis, asthma, lupus, allograft rejection, anti-tumour immunity and recently psoriasis,{{cite journal | vauthors = Aggarwal S, Gurney AL | title = IL-17: prototype member of an emerging cytokine family | journal = Journal of Leukocyte Biology | volume = 71 | issue = 1 | pages = 1–8 | date = January 2002 | doi = 10.1189/jlb.71.1.1 | pmid = 11781375 | s2cid = 15271840 | doi-access = free }} multiple sclerosis,{{cite journal | vauthors = Paul O, Bland EF, Massell BF | title = T. Duckett Jones and his association with Paul Dudley White | journal = Clinical Cardiology | volume = 13 | issue = 5 | pages = 367–9 | date = May 1990 | pmid = 2189615 | doi = 10.1002/clc.4960130511 | s2cid = 45530740 | doi-access = free }} and intracerebral hemorrhage.{{cite journal | vauthors = Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, Che F, Chen X, Ren H, Hong M, Wang J | display-authors = 6 | title = Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage | journal = Progress in Neurobiology | volume = 178 | pages = 101610 | date = July 2019 | pmid = 30923023 | doi = 10.1016/j.pneurobio.2019.03.003 | s2cid = 85495400 }}

The gene for human IL-17A is 1874 base pairs long{{cite journal | vauthors = Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Spriggs MK, Armitage RJ | title = Human IL-17: a novel cytokine derived from T cells | journal = Journal of Immunology | volume = 155 | issue = 12 | pages = 5483–6 | date = December 1995 | doi = 10.4049/jimmunol.155.12.5483 | pmid = 7499828 | url = http://www.jimmunol.org/cgi/content/abstract/155/12/5483 | doi-access = free }} and was 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 appear 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, although in resting conditions is low in abundance. 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.

Much progress has been made in the understanding of the regulation of IL-17. At first, Aggarwal et al. showed that production of IL-17 was dependent on IL-23.{{cite journal | vauthors = Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL | title = Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 3 | pages = 1910–4 | date = January 2003 | pmid = 12417590 | doi = 10.1074/jbc.M207577200 | doi-access = free}} Later, a Korean group discovered that STAT3 and NF-κB signalling pathways are required for this IL-23-mediated IL-17 production.{{cite journal | vauthors = Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB, Jin HT, Min SY, Ju JH, Park KS, Cho YG, Yoon CH, Park SH, Sung YC, Kim HY | display-authors = 6 | title = STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice | journal = Journal of Immunology | volume = 176 | issue = 9 | pages = 5652–61 | date = May 2006 | pmid = 16622035 | doi = 10.4049/jimmunol.176.9.5652 | url = http://www.jimmunol.org/cgi/content/abstract/176/9/5652 | doi-access = free }} Consistent with this finding, Chen et al. showed that another molecule, SOCS3, plays an important role in IL-17 production.{{cite journal | vauthors = Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O'Shea JJ | display-authors = 6 | title = Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 21 | pages = 8137–42 | date = May 2006 | pmid = 16698929 | pmc = 1459629 | doi = 10.1073/pnas.0600666103 | bibcode = 2006PNAS..103.8137C | doi-access = free }} In the absence of SOCS3, IL-23-induced STAT3 phosphorylation is enhanced, and phosphorylated STAT3 binds to the promoter 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 groups have identified ways to induce IL-17 production both in vitro{{cite journal | vauthors = Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B | title = TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells | journal = Immunity | volume = 24 | issue = 2 | pages = 179–89 | date = February 2006 | pmid = 16473830 | doi = 10.1016/j.immuni.2006.01.001 | doi-access = free }} and in vivo{{cite journal | vauthors = Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT | display-authors = 6 | title = Transforming growth factor-beta induces development of the T(H)17 lineage | journal = Nature | volume = 441 | issue = 7090 | pages = 231–4 | date = May 2006 | pmid = 16648837 | doi = 10.1038/nature04754 | s2cid = 4379904 | bibcode = 2006Natur.441..231M | doi-access = free }}{{cite journal | vauthors = Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK | display-authors = 6 | title = Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells | journal = Nature | volume = 441 | issue = 7090 | pages = 235–8 | date = May 2006 | pmid = 16648838 | doi = 10.1038/nature04753 | s2cid = 4391497 | bibcode = 2006Natur.441..235B }} by distinct cytokines, called TGF-β and IL-6, without the need for IL-23. Although 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. Recently, Ivanov et al. found that the thymus specific nuclear receptor, ROR-γ, directs differentiation of IL-17-producing T cells.{{cite journal | vauthors = Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR | display-authors = 6 | title = The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells | journal = Cell | volume = 126 | issue = 6 | pages = 1121–33 | date = September 2006 | pmid = 16990136 | doi = 10.1016/j.cell.2006.07.035 | s2cid = 9034013 | doi-access = free }}

IL-17(A) is a 155-amino acid protein that is a disulfide-linked, homodimeric, secreted glycoprotein with a molecular mass of 35 kDa. Each subunit of the homodimer is approximately 15-20 KDa. The structure of IL-17 consists of a signal peptide of 23 amino acids (aa) followed by a 123-aa chain region characteristic of the IL-17 family. An N-linked glycosylation site on the protein was first identified after purification of the protein revealed two bands, one at 15 KDa and another at 20 KDa. Comparison of different members of the IL-17 family revealed four conserved cysteines that form two disulfide bonds. IL-17 is unique in that it bears no resemblance to other known interleukins. Furthermore, IL-17 bears no resemblance to any other known proteins or structural domains.

The crystal structure of IL-17F, which is 50% homologous to IL-17A, revealed that IL-17F is structurally similar to the cystine knot family of proteins that includes the neurotrophins. The cystine knot fold is characterized by two sets of paired β-strands stabilized by three disulfide interactions. However, in contrast to the other cystine knot proteins, IL-17F lacks the third disulfide bond. Instead, a serine replaces the cysteine at this position. This unique feature is conserved in the other IL-17 family members. IL-17F also dimerizes in a fashion similar to nerve growth factor (NGF) and other neurotrophins.

Recent work suggests the IL-23/IL-17 pathway plays a major role in the autoimmune disorder psoriasis.{{cite journal | vauthors = Lowes MA, Suárez-Fariñas M, Krueger JG | title = Immunology of psoriasis | journal = Annual Review of Immunology | volume = 32 | pages = 227–55 | year = 2014 | pmid = 24655295 | pmc = 4229247 | doi = 10.1146/annurev-immunol-032713-120225 }}{{cite journal | vauthors = Hu Y, Shen F, Crellin NK, Ouyang W | title = The IL-17 pathway as a major therapeutic target in autoimmune diseases | journal = Annals of the New York Academy of Sciences | volume = 1217 | issue = 1 | pages = 60–76 | date = January 2011 | pmid = 21155836 | doi = 10.1111/j.1749-6632.2010.05825.x | s2cid = 20349222 | bibcode = 2011NYASA1217...60H }} In this condition, immune cells react to inflammatory molecules released within the skin around the joints and scalp. This response causes the epidermal cells to recycle more rapidly than usual, which leads to the formation of red, scaly lesions and chronic skin inflammation.{{cite journal | vauthors = Baliwag J, Barnes DH, Johnston A | title = Cytokines in psoriasis | journal = Cytokine | volume = 73 | issue = 2 | pages = 342–50 | date = June 2015 | pmid = 25585875 | pmc = 4437803 | doi = 10.1016/j.cyto.2014.12.014 }} Analysis of biopsies taken from lesions of psoriasis patients show an enrichment of cytotoxic T cells and neutrophils containing IL-17.{{cite journal | vauthors = Mudigonda P, Mudigonda T, Feneran AN, Alamdari HS, Sandoval L, Feldman SR | title = Interleukin-23 and interleukin-17: importance in pathogenesis and therapy of psoriasis | journal = Dermatology Online Journal | volume = 18 | issue = 10 | pages = 1 | date = October 2012 | doi = 10.5070/D33N39N8XM | pmid = 23122008 | url = http://escholarship.org/uc/item/3n39n8xm }}{{cite journal | vauthors = Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S, Villanueva EC, Shah P, Kaplan MJ, Bruce AT | display-authors = 6 | title = Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis | journal = Journal of Immunology | volume = 187 | issue = 1 | pages = 490–500 | date = July 2011 | pmid = 21606249 | pmc = 3119764 | doi = 10.4049/jimmunol.1100123 }} This indicates an excessive infiltration of pro-inflammatory immune cells and IL-17 cytokines are associated with the development of psoriasis.

Studies conducted in mice demonstrate that removing either IL-23 or IL-17 decreases the progression of psoriasis.{{cite journal | vauthors = Nakajima K, Kanda T, Takaishi M, Shiga T, Miyoshi K, Nakajima H, Kamijima R, Tarutani M, Benson JM, Elloso MM, Gutshall LL, Naso MF, Iwakura Y, DiGiovanni J, Sano S | display-authors = 6 | title = Distinct roles of IL-23 and IL-17 in the development of psoriasis-like lesions in a mouse model | journal = Journal of Immunology | volume = 186 | issue = 7 | pages = 4481–9 | date = April 2011 | pmid = 21346238 | doi = 10.4049/jimmunol.1000148 | doi-access = free }}{{cite journal | vauthors = Krueger JG, Fretzin S, Suárez-Fariñas M, Haslett PA, Phipps KM, Cameron GS, McColm J, Katcherian A, Cueto I, White T, Banerjee S, Hoffman RW | display-authors = 6 | title = IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis | journal = The Journal of Allergy and Clinical Immunology | volume = 130 | issue = 1 | pages = 145–54.e9 | date = July 2012 | pmid = 22677045 | pmc = 3470466 | doi = 10.1016/j.jaci.2012.04.024 }} Mice injected with monoclonal antibodies targeting IL-17 blocked, or neutralized, down-stream signaling of this cytokine and decreased epidermal hyperplasia. Similarly, mice genetically modifying to not express IL-23 or IL-17 receptors significantly reduced psoriatic lesion development upon stimulation with the lesion-causing tumor promoter 12-O-tetradecanoylphorbol-13-acetate.

IL-17 promotes psoriasis by contributing to the inflammatory response that damages and overturns the keratinocyte cells of the epidermal layer. Inflammation begins with keratinocyte cells entering the final stages of their cell cycle, which activates immature dendritic cells (DC).{{cite journal | vauthors = Dombrowski Y, Schauber J | title = Cathelicidin LL-37: a defense molecule with a potential role in psoriasis pathogenesis | journal = Experimental Dermatology | volume = 21 | issue = 5 | pages = 327–30 | date = May 2012 | pmid = 22509827 | doi = 10.1111/j.1600-0625.2012.01459.x | s2cid = 24119451 }} Cytokines released from DCs stimulate dying keratinocytes to secrete TNF-alpha, IL-1 and IL-6 leading to the chemotaxis of T cells, natural killer cells and monocytes to the epidermis. These cells release IL-23 which induce Th17 cells to produce IL-17.

IL-17 interaction with IL-17RA receptors, abundant on the keratinocyte cell surface, incite epidermal cells to increase expression of IL-6, antimicrobial peptides, IL-8 and CCL20. Increased concentration of IL-6 alters the epidermal environment by decreasing the ability of T regulatory cells to control the behavior of Th17 cells. Reduced regulation allows uninhibited proliferation of Th17 cells and production of IL-17 in psoriatic lesions, augmenting IL-17 signaling. Antimicrobial peptides and IL-8 attract neutrophils to the site of injury where these cells remove damaged and inflamed keratinocyte cells. New immature DCs are also recruited by CCL20 via chemotaxis where their activation restarts and amplifies the cycle of inflammation. IL-17 and additional cytokines released from the influx of neutrophils, T and dendritic cells mediate effects on localized leukocytes and keratinocytes that supports the progression of psoriasis by inciting chronic inflammation.

The IL-17F gene was discovered in 2001 and is located on chromosome 6p12. Notably, among this family, IL-17F has been well characterized both in vitro and in vivo and has been shown to have a pro-inflammatory role in asthma. IL-17F is clearly expressed in the airway of asthmatics and its expression level is correlated with disease severity. Moreover, a coding region variant (H161R) of the IL-17F gene is inversely associated with asthma and encodes an antagonist for the wild-type IL-17F. IL-17F is able to induce several cytokines, chemokines and adhesion molecules in bronchial epithelial cells, vein endothelial cells, fibroblasts and eosinophils. IL-17F utilizes IL-17RA and IL-17RC as its receptors and activates the MAP kinase-related pathway. IL-17F is derived from several cell types such as Th17 cells, mast cells and basophils, and shows a wide tissue expression pattern including lung. Overexpression of IL-17F gene in the airway of mice is associated with airway neutrophilia, the induction of many cytokines, an increase in airway hyperreactivity, and mucus hypersecretion. Hence, IL-17F may have a crucial role in allergic airway inflammation and have important therapeutic implications in asthma.{{cite journal | vauthors = Kawaguchi M, Kokubu F, Fujita J, Huang SK, Hizawa N | title = Role of interleukin-17F in asthma | journal = Inflammation & Allergy - Drug Targets | volume = 8 | issue = 5 | pages = 383–9 | date = December 2009 | pmid = 20025586 | doi = 10.2174/1871528110908050383 }}

Because of its involvement in immune regulatory functions, IL-17 inhibitors are being investigated as possible treatments for autoimmune diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease.{{cite journal | vauthors = Carbonell F, Heimpel H, Kubanek B, Fliedner TM | title = Growth and cytogenetic characteristics of bone marrow colonies from patients with 5q-syndrome | journal = Blood | volume = 66 | issue = 2 | pages = 463–5 | date = August 1985 | pmid = 4016279 | doi = 10.1182/blood.V66.2.463.463 | doi-access = free }}{{cite journal | vauthors = Cleve H, Kirk RL, Gajdusek DC, Guiart J | title = On the distribution of the Gc variant Gc Aborigine in Melanesian populations; determination of Gc-types in sera from Tongariki Island, New Hebrides | journal = Acta Genetica et Statistica Medica | volume = 17 | issue = 6 | pages = 511–7 | year = 1967 | pmid = 4168861 | doi = 10.1159/000152104 }}{{cite journal | vauthors = Seppälä M, Rönnberg L, Karonen SL, Kauppila A | title = Micronized oral progesterone increases the circulating level of endometrial secretory PP14/beta-lactoglobulin homologue | journal = Human Reproduction | volume = 2 | issue = 6 | pages = 453–5 | date = August 1987 | pmid = 3312283 | doi = 10.1093/oxfordjournals.humrep.a136569 }} In January 2015, the FDA approved the use of secukinumab (trade name Cosentyx), an IL-17 inhibiting monoclonal antibody, for the treatment of moderate to severe plaque psoriasis.{{Cite web | title = FDA approves new psoriasis drug Cosentyx | date = 2015-01-21 | access-date = 2015-03-12 | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm430969.htm | publisher = U.S. Food and Drug Administration }} In addition, Cosentyx has been approved in Japan for use in treating psoriatic arthritis.{{Cite web | title = First in the world regulatory approval of Novartis' Cosentyx(TM) in Japan for both psoriasis and psoriatic arthritis | date = 2014-12-26 | access-date = 2015-03-12 | url = http://www.novartis.com/newsroom/media-releases/en/2014/1883568.shtml | publisher = Novartis AG | archive-date = 2015-03-25 | archive-url = https://web.archive.org/web/20150325151419/http://www.novartis.com/newsroom/media-releases/en/2014/1883568.shtml | url-status = dead }} The anti-IL-23 antibody ustekinumab can also be used to effectively treat psoriasis by indirectly reducing IL-17.{{cite journal | vauthors = Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB | display-authors = 6 | title = Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1) | journal = Lancet | volume = 371 | issue = 9625 | pages = 1665–74 | date = May 2008 | pmid = 18486739 | doi = 10.1016/S0140-6736(08)60725-4 | s2cid = 24055733 }}

Based on emerging evidence from animal models, IL-17 has been suggested as a target for anti-inflammatory therapies to improve recovery post-stroke{{cite journal | vauthors = Swardfager W, Winer DA, Herrmann N, Winer S, Lanctôt KL | title = Interleukin-17 in post-stroke neurodegeneration | journal = Neuroscience and Biobehavioral Reviews | volume = 37 | issue = 3 | pages = 436–47 | date = March 2013 | pmid = 23370232 | doi = 10.1016/j.neubiorev.2013.01.021 | s2cid = 10722525 }} and to reduce the formation of skin cancer.{{cite journal | vauthors = Ortiz ML, Kumar V, Martner A, Mony S, Donthireddy L, Condamine T, Seykora J, Knight SC, Malietzis G, Lee GH, Moorghen M, Lenox B, Luetteke N, Celis E, Gabrilovich D | display-authors = 6 | title = Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4+ T cells | journal = The Journal of Experimental Medicine | volume = 212 | issue = 3 | pages = 351–67 | date = March 2015 | pmid = 25667306 | pmc = 4354367 | doi = 10.1084/jem.20140835 }} IL-17 has also been implicated in multiple sclerosis.

The active form of vitamin D has been found to 'severely impair' {{cite journal | vauthors = Chang SH, Chung Y, Dong C | title = Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression | journal = The Journal of Biological Chemistry | volume = 285 | issue = 50 | pages = 38751–5 | date = December 2010 | pmid = 20974859 | pmc = 2998156 | doi = 10.1074/jbc.C110.185777 | doi-access = free }} production of the IL-17 and IL-17F cytokines by Th17 cells.

{{see also|Interleukin-17 receptor}}

The IL-17 receptor family consists of five, broadly distributed receptors (IL-17RA, B, C, D and E) that present with individual ligand specificities. 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.{{cite journal | vauthors = Kawaguchi M, Adachi M, Oda N, Kokubu F, Huang SK | title = IL-17 cytokine family | journal = The Journal of Allergy and Clinical Immunology | volume = 114 | issue = 6 | pages = 1265–73; quiz 1274 | date = December 2004 | pmid = 15577820 | doi = 10.1016/j.jaci.2004.10.019 | doi-access = free }} 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.{{cite journal | vauthors = Pappu R, Ramirez-Carrozzi V, Sambandam A | title = The interleukin-17 cytokine family: critical players in host defence and inflammatory diseases | journal = Immunology | volume = 134 | issue = 1 | pages = 8–16 | date = September 2011 | pmid = 21726218 | pmc = 3173690 | doi = 10.1111/j.1365-2567.2011.03465.x }}

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 a 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 least-described of these receptors, IL-17RE, is known to be expressed in the pancreas, brain, and prostate.

Signal transduction by these receptors is as diverse as their distribution. These receptors do not exhibit a significant similarity in extracellular or intracellular amino acid sequence when compared to other cytokine receptors. Transcription factors such as TRAF6, JNK, Erk1/2, p38, AP-1 and NF-κB have been implicated in IL-17 mediated signaling in a stimulation-dependent, tissue-specific manner.{{cite journal | vauthors = Ley K, Smith E, Stark MA | title = IL-17A-producing neutrophil-regulatory Tn lymphocytes | journal = Immunologic Research | volume = 34 | issue = 3 | pages = 229–42 | year = 2006 | pmid = 16891673 | doi = 10.1385/IR:34:3:229 | s2cid = 22008293 }} Other signaling mechanisms have also been proposed, but more work is needed to fully elucidate the true signaling pathways used by these diverse receptors.

{{Reflist|33em}}

{{Interleukins}}

{{Interleukin receptor modulators}}

Category:Interleukins