Interleukin 17

2019-01-05T09:42:37Z

176.123.121.234: /* Gene expression */

{{infobox protein
| Name = [[IL17A|Interleukin 17A]]
| caption =
| image =
| width =
| HGNCid = 5981
| Symbol = [[IL17A]]
| AltSymbols = IL17, CTLA8
| EntrezGene = 3605
| OMIM = 603149
| RefSeq = NP_002181
| UniProt = Q16552
| PDB =
| ECnumber =
| Chromosome = 6
| Arm = p
| Band = 12
| LocusSupplementaryData =
}}
{{infobox protein
| Name = Interleukin 17B
| caption =
| image =
| width =
| HGNCid = 5982
| Symbol = IL17B
| AltSymbols = ZCOTO7
| EntrezGene = 27190
| OMIM = 604627
| RefSeq = NP_055258
| UniProt = Q9UHF5
| PDB =
| ECnumber =
| Chromosome = 5
| Arm = q
| Band = 32-34
| LocusSupplementaryData =
}}
{{infobox protein
| Name = Interleukin 17C
| caption =
| image =
| width =
| HGNCid = 5983
| Symbol = IL17C
| AltSymbols = , CX2
| EntrezGene = 271989
| OMIM = 604628
| RefSeq = NP_037410
| UniProt = Q9P0M4
| PDB =
| ECnumber =
| Chromosome = 16
| Arm = q
| Band = 24
| LocusSupplementaryData =
}}
{{infobox protein
| Name = Interleukin 17D
| caption =
| image =
| width =
| HGNCid = 5984
| Symbol = IL17D
| AltSymbols =
| EntrezGene = 53342
| OMIM = 607587
| RefSeq = NP_612141
| UniProt = Q8TAD2
| PDB =
| ECnumber =
| Chromosome = 13
| Arm = q
| Band = 11
| LocusSupplementaryData =
}}
{{infobox protein
| Name = Interleukin 17E
| caption =
| image =
| width =
| HGNCid = 13765
| Symbol = IL17E
| AltSymbols = [[Interleukin 25|IL-25]]
| EntrezGene = 64806
| OMIM = 605658
| RefSeq = NP_073626
| UniProt = Q9H293
| PDB =
| ECnumber =
| Chromosome = 14
| Arm = q
| Band = 11.2
| LocusSupplementaryData =
}}
{{infobox protein
| Name = Interleukin 17F
| caption = [[X-ray crystallography#Biological macromolecular crystallography|Crystallographic structure]] of dimeric human IL-17f.<ref name="pmid11574464">{{PDB|1JPY}}; {{cite journal | vauthors = Hymowitz SG, Filvaroff EH, Yin JP, Lee J, Cai L, Risser P, Maruoka M, Mao W, Foster J, Kelley RF, Pan G, Gurney AL, de Vos AM, Starovasnik MA | title = IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding | journal = EMBO J. | volume = 20 | issue = 19 | pages = 5332–41 |date=October 2001 | pmid = 11574464 | pmc = 125646 | doi = 10.1093/emboj/20.19.5332 | url = }}</ref>
| image = IL17F_1JPY.png
| width =
| HGNCid = 16404
| Symbol = IL17F
| AltSymbols = ML-1
| EntrezGene = 112744
| OMIM = 606496
| RefSeq = NP_443104
| UniProt = Q96PD4
| PDB = 1JPY
| ECnumber =
| Chromosome = 6
| Arm = p
| Band = 12
| LocusSupplementaryData =
}}
'''Interleukin 17A''' ('''IL-17''' or '''IL-17A''') is a pro-inflammatory [[cytokine]]. This cytokine is produced by a group of [[T-helper cells|T helper cell]] known as [[Th17 cells|T helper 17 cell]] in response to their stimulation with [[Interleukin 23|IL-23]]. Originally, Th17 was identified in 1993 by Rouvier ''et al.'' who isolated IL17 [[Transcription (genetics)|transcript]] from a [[rodent]] [[T-cell]] [[hybridoma]]. The protein encoded by ''IL17A'' is a founding member of [[IL-17 family]] (see below). IL17 protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic [[rhadinovirus]] ''Herpesvirus saimiri''.<ref name="pmid8390535">{{cite journal | vauthors = Rouvier E, Luciani MF, Mattéi MG, Denizot F, Golstein P | title = CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene | journal = Journal of Immunology | volume = 150 | issue = 12 | pages = 5445–56 | date = Jun 1993 | pmid = 8390535 | doi = | url = http://www.jimmunol.org/cgi/content/abstract/150/12/5445 }}</ref> In rodents, IL-17 is often referred to as CTLA8.

The biologically active IL-17 interacts with type I cell surface receptor [[interleukin-17 receptor|IL-17R]]. In turn, there are at least three variants of IL-17R referred to as [[IL17RA]], [[IL17RB]], and [[IL17RC]].<ref name="pmid12097364">{{cite journal | vauthors = Starnes T, Broxmeyer HE, Robertson MJ, Hromas R | title = Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis | journal = Journal of Immunology | volume = 169 | issue = 2 | pages = 642–6 | date = Jul 2002 | pmid = 12097364 | doi = 10.4049/jimmunol.169.2.642 | url = http://www.jimmunol.org/cgi/content/abstract/169/2/642 }}</ref> After binding to the receptor, IL-17 activates several signalling cascades that, in turn, lead to the induction of chemokines. Acting as chemoattractants, these chemokines recruit the immune cells, such as monocytes and neutrophils to the site of inflammation. Typically, the 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]].<ref>{{cite journal | vauthors = Chiricozzi A, Guttman-Yassky E, Suárez-Fariñas M, Nograles KE, Tian S, Cardinale I, Chimenti S, Krueger JG | title = Integrative responses to IL-17 and TNF-α in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis | journal = The Journal of Investigative Dermatology | volume = 131 | issue = 3 | pages = 677–87 | date = Mar 2011 | pmid = 21085185 | doi = 10.1038/jid.2010.340 }}</ref><ref name="pmid19710487">{{cite journal | vauthors = Miossec P, Korn T, Kuchroo VK | title = Interleukin-17 and type 17 helper T cells | journal = The New England Journal of Medicine | volume = 361 | issue = 9 | pages = 888–98 | date = Aug 2009 | pmid = 19710487 | doi = 10.1056/NEJMra0707449 }}</ref> Moreover, an activation of IL-17 signalling is often observed in the pathogenesis of various autoimmune disorders, such as [[psoriasis]].<ref name="Martin_2013">{{cite journal | vauthors = Martin DA, Towne JE, Kricorian G, Klekotka P, Gudjonsson JE, Krueger JG, Russell CB | title = The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings | journal = The Journal of Investigative Dermatology | volume = 133 | issue = 1 | pages = 17–26 | year = 2013 | pmid = 22673731 | pmc = 3568997 | doi = 10.1038/jid.2012.194 }}</ref>

== Family members ==
The IL-17 family comprises [[IL-17A|IL17A]], IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. IL-17E is also known as [[interleukin 25|IL-25]]. All members of the IL-17 family have a similar [[protein]] structure. Their protein sequences contain four highly conserved [[cysteine]] residues. These concerved cysteine residues are critical to the right [[Three-dimensional space|3-dimensional]] shape of the entire protein molecule. To the reference, the members of 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 follow by IL-17B, which has 29% similarity to IL-17A, IL-17D (25%), IL-17C (23%), and IL-17E (17%). In [[mammal]]s, 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%.<ref name="Kolls2004">{{cite journal | vauthors = Kolls JK, Lindén A | title = Interleukin-17 family members and inflammation | journal = Immunity | volume = 21 | issue = 4 | pages = 467–76 | date = Oct 2004 | pmid = 15485625 | doi = 10.1016/j.immuni.2004.08.018 }}</ref>

== Function ==
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 [[Interleukin 6|IL-6]], [[G-CSF]], [[GM-CSF]], [[interleukin-1|IL-1β]], [[TGF-β]], [[TNF-α]]), [[chemokines]] (including [[Interleukin 8|IL-8]], GRO-α, and MCP-1), and [[prostaglandins]] (e.g., [[Prostaglandin E|PGE]]<sub>2</sub>) from many cell types ([[fibroblasts]], [[endothelial cells]], [[epithelial cells]], [[keratinocytes]], and [[macrophages]]). IL-17 acts with [[Interleukin 22|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 essential to a subset of [[CD4]]+ T-Cells called [[T helper 17 cell|T helper 17]] (T<sub>h</sub>17) cells. As a result of these roles, the IL-17 family has been linked to many immune/autoimmune related diseases including [[rheumatoid arthritis]], [[asthma]], [[lupus erythematosus|lupus]], [[allograft]] rejection, anti-tumour immunity and recently [[psoriasis]]<ref name="aggaral">{{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 = Jan 2002 | pmid = 11781375 | doi = | url = http://www.jleukbio.org/cgi/content/abstract/71/1/1 }}</ref> and [[multiple sclerosis]].<ref name="ReferenceA">{{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}}</ref>

==Gene expression ==
The [[gene]] for human IL-17 is 1874 [[base pair]]s long<ref name="Yao1995">{{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 = Dec 1995 | pmid = 7499828 | doi = | url = http://www.jimmunol.org/cgi/content/abstract/155/12/5483 }}</ref> and was cloned from CD4+ T cells. Each member of the IL-17 family has a distinct pattern of cellular [[gene expression|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 [[Inflammation|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.<ref name = "aggaral"/>

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 [[interleukin 23|IL-23]].<ref name="pmid12417590">{{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 = Jan 2003 | pmid = 12417590 | doi = 10.1074/jbc.M207577200 }}</ref> Later, a Korean group discovered that [[STAT protein|STAT3]] and [[NF-κB]] signalling pathways are required for this IL-23-mediated IL-17 production.<ref name="pmid16622035">{{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 | 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 }}</ref> Consistent with this finding, Chen ''et al.'' showed that another molecule, [[SOCS3]], plays an important role in IL-17 production.<ref name="pmid16698929">{{cite journal | vauthors = Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O'Shea JJ | 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 }}</ref> In the absence of SOCS3, IL-23-induced STAT3 [[phosphorylation]] is enhanced, and phosphorylated STAT3 binds to the [[promoter (biology)|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 groups have identified ways to induce IL-17 production both ''in vitro''<ref name="Veldhoen2006">{{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 = Feb 2006 | pmid = 16473830 | doi = 10.1016/j.immuni.2006.01.001 }}</ref> and ''in vivo''<ref name="Mangan2006">{{cite journal | vauthors = Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT | 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 }}</ref><ref name="Bettelli2006">{{cite journal | vauthors = Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK | 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 }}</ref> by distinct cytokines, called [[TGF-β]] and [[Interleukin 6|IL-6]], without the need for IL-23.<ref name="Veldhoen2006"/><ref name="Mangan2006"/><ref name="Bettelli2006"/> 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-cell]]s. Recently, Ivanov ''et al.'' found that the [[thymus]] specific [[nuclear receptor]], [[RAR-related orphan receptor gamma|ROR-γ]], directs differentiation of IL-17-producing T cells.<ref>{{cite journal | vauthors = Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR | title = The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells | journal = Cell | volume = 126 | issue = 6 | pages = 1121–1133 | date = Sep 2006 | pmid = 16990136 | doi = 10.1016/j.cell.2006.07.035 }}</ref>

== Structure ==
IL-17(A) is a 155-amino acid protein that is a [[disulfide]]-linked, [[protein dimer|homodimeric]], secreted [[glycoprotein]] with a molecular mass of 35 kDa.<ref name="Kolls2004"/> 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 bond]]s.<ref name="Yao1995"/> IL-17 is unique in that it bears no resemblance to other known [[interleukin]]s. Furthermore, IL-17 bears no resemblance to any other known proteins or structural domains.<ref name="aggaral"/>

The crystal structure of IL-17F, which is 50% homologous to IL-17A, revealed that IL-17F is structurally similar to the cysteine knot family of proteins that includes the [[neurotrophin]]s. The [[cysteine knot]] fold is characterized by two sets of paired [[β-strand]]s stabilized by three disulfide interactions. However, in contrast to the other cysteine 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.<ref name="pmid11574464" />

==Role in psoriasis==
Recent work suggests the IL-25/IL-17 pathway plays a major role in the autoimmune disorder [[psoriasis]].<ref name="Martin_2013"/><ref name="Lowes_2014">{{cite journal | vauthors = Lowes MA, Suárez-Fariñas M, Krueger JG | title = Immunology of psoriasis | journal = Annual Review of Immunology | volume = 32 | issue = | pages = 227–55 | year = 2014 | pmid = 24655295 | pmc = 4229247 | doi = 10.1146/annurev-immunol-032713-120225 }}</ref><ref name="Hu_2011">{{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 = | pages = 60–76 | year = 2011 | pmid = 21155836 | doi = 10.1111/j.1749-6632.2010.05825.x }}</ref> In this condition, immune cells react to inflammatory molecules released within the skin around the joints and scalp.<ref name="Lowes_2014" /> 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.<ref name="Hu_2011" /><ref name="Baliwag_2015">{{cite journal | vauthors = Baliwag J, Barnes DH, Johnston A | title = Cytokines in psoriasis | journal = Cytokine | volume = 73 | issue = 2 | pages = 342–50 | year = 2015 | pmid = 25585875 | doi = 10.1016/j.cyto.2014.12.014 | pmc=4437803}}</ref> Analysis of biopsies taken from lesions of psoriasis patients show an enrichment of cytotoxic T cells and neutrophils containing IL-17.<ref name="Lowes_2014" /><ref name="Mudigonda_2012">{{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 | year = 2012 | pmid = 23122008 | doi = | url = http://escholarship.org/uc/item/3n39n8xm }}</ref><ref name="Mudigonda_2012" /><ref name="Lin_2011">{{cite journal | vauthors = Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S, Villanueva EC, Shah P, Kaplan MJ, Bruce AT | 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 | year = 2011 | pmid = 21606249 | pmc = 3119764 | doi = 10.4049/jimmunol.1100123 }}</ref> 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-25 or IL-17 decreases the progression of psoriasis.<ref name="Nakajima_2011">{{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 | title = Distinct roles of IL-25 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 | year = 2011 | pmid = 21346238 | doi = 10.4049/jimmunol.1000148 }}</ref><ref name="Krueger_2012">{{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 | 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 | year = 2012 | pmid = 22677045 | pmc = 3470466 | doi = 10.1016/j.jaci.2012.04.024 }}</ref> Mice injected with [[monoclonal antibodies]] targeting IL-17 blocked, or neutralized, down stream signaling of this cytokine and decreased epidermal [[hyperplasia]].<ref name="Nakajima_2011" /> Similarly, genetically modifying mice 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.<ref name="Martin_2013" />

IL-17 promotes psoriasis by contributing to the inflammatory response that damages and overturns the [[keratinocyte]] cells of the epidermal layer.<ref name="Lowes_2014" /><ref name="Krueger_2012" /> Inflammation begins with keratinocyte cells entering the final stages of their cell cycle, which activates immature [[dendritic cell]]s (DC).<ref>{{Cite journal|url = |title = Cathelicidin LL-37: a defense molecule with a potential role in psoriasis pathogenesis|last = Dombrowski|first = |date = 2012|journal = Experimental Dermatology|doi = 10.1111/j.1600-0625.2012.01459.x|pmid = |access-date = |volume=21 |pages=327–330}}</ref> Cytokines released from DCs stimulate dying keratinocytes to secrete [[TNF-alpha]], [[Interleukin 1|IL-1]] and [[Interleukin 6|IL-6]] leading to the [[chemotaxis]] of [[T cells]], [[natural killer cells]] and [[monocytes]] to the epidermis.<ref name="Baliwag_2015" /> These cells release IL-23 which induce [[T helper 17 cell|Th17]] cells to produce IL-17.<ref name="Mudigonda_2012"/>

IL-17 interaction with IL-17RA receptors, abundant on the keratinocyte cell surface, incite epidermal cells to increase expression of IL-6, [[antimicrobial peptides]], [[Interleukin 8|IL-8]] and [[CCL20]].<ref name="Martin_2013"/><ref name="Hu_2011" /><ref name="Krueger_2012" /> Increased concentration of IL-6 alters the epidermal environment by decreasing the ability of [[T-reg|T regulatory cells]] to control the behavior of [[T helper 17 cell|Th17]] cells.<ref name="Mudigonda_2012"/> Reduced regulation allows uninhibited proliferation of Th17 cells and production of IL-17 in psoriatic lesions, augmenting IL-17 signaling.<ref name="Mudigonda_2012"/> Antimicrobial peptides and IL-8 attract neutrophils to the site of injury where these cells remove damaged and inflamed keratinocyte cells.<ref name="Lowes_2014" /><ref name="Lin_2011" /><ref name="Krueger_2012" /> New immature DCs are also recruited by CCL20 via chemotaxis where their activation restarts and amplifies the cycle of inflammation.<ref name="Mudigonda_2012" /><ref name="Lin_2011" /> 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.<ref name="Mudigonda_2012"/>

== Role in asthma ==
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 [[MAPK/ERK pathway|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.<ref name="pmid20025586">{{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 = Dec 2009 | pmid = 20025586 | doi = 10.2174/1871528110908050383 }}</ref>

==Therapeutic target==
Because of its involvement in immune regulatory functions, IL-17 inhibitors are being investigated as possible treatments for [[autoimmune disease]]s such as [[rheumatoid arthritis]], [[psoriasis]] and [[inflammatory bowel disease]].<ref>{{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 = Aug 1985 | pmid = 4016279 }}</ref><ref>{{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 | pmid = 4168861 | year = 1967 | doi=10.1159/000152104}}</ref><ref>{{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 = Aug 1987 | pmid = 3312283 | doi = 10.1093/oxfordjournals.humrep.a136569 }}</ref> In January 2015, the FDA approved the use of [[secukinumab]] (trade name [[secukinumab|Cosentyx]]), an IL-17 inhibiting [[monoclonal antibody]], for the treatment of moderate to severe plaque psoriasis.<ref>{{Cite web | title = FDA approves new psoriasis drug Cosentyx | date = 2015-01-21 | accessdate = 2015-03-12 | url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm430969.htm | publisher = U.S. Food and Drug Administration }}</ref> In addition, Cosentyx has been approved in Japan for use in treating [[psoriatic arthritis]].<ref>{{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 | accessdate = 2015-03-12 | url = http://www.novartis.com/newsroom/media-releases/en/2014/1883568.shtml | publisher = Novartis AG }}</ref> The anti-IL-23 antibody [[ustekinumab]] can also be used to effectively treat psoriasis by reducing IL-17.<ref>{{cite journal | vauthors = Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB | 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 }}</ref>

Based on emerging evidence from animal models, IL-17 has been suggested as a target for anti-inflammatory therapies to improve recovery post-stroke<ref>{{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 = Mar 2013 | pmid = 23370232 | doi = 10.1016/j.neubiorev.2013.01.021 }}</ref> and to reduce the formation of skin cancer.<ref>{{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 | 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 = Mar 2015 | pmid = 25667306 | pmc = 4354367 | doi = 10.1084/jem.20140835 }}</ref> IL-17 has also been implicated in [[multiple sclerosis]].<ref name="ReferenceA"/>

The active form of [[vitamin D]] has been found to 'severely impair' <ref>{{cite journal|last1=Chang|first1=Seon Hee|last2=Chung|first2=Yeonseok|last3=Dong|first3=Chen|title=Vitamin D Suppresses Th17 Cytokine Production by Inducing C/EBP Homologous Protein (CHOP) Expression|journal=The Journal of Biological Chemistry|date=10 December 2010|volume=285|issue=50|pages=38751–38755|doi=10.1074/jbc.C110.185777|issn=0021-9258|pmc=2998156|pmid=20974859}}</ref> production of the [[IL17A|IL-17]] and [[Interleukin 17#Family members|IL-17F]] cytokines by [[T helper 17 cell|Th17]] cells.

== Receptors ==
{{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.<ref name="Kolls2004"/><ref name="Kawaguchi2004">{{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 = Dec 2004 | pmid = 15577820 | doi = 10.1016/j.jaci.2004.10.019 }}</ref><ref name="Moseley2003">{{cite journal | vauthors = Moseley TA, Haudenschild DR, Rose L, Reddi AH | title = Interleukin-17 family and IL-17 receptors | journal = Cytokine & Growth Factor Reviews | volume = 14 | issue = 2 | pages = 155–74 | date = Apr 2003 | pmid = 12651226 | doi = 10.1016/S1359-6101(03)00002-9 }}</ref> 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.<ref name="pmid21726218">{{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 = Sep 2011 | pmid = 21726218 | pmc = 3173690 | doi = 10.1111/j.1365-2567.2011.03465.x }}</ref>

Another member of this receptor family, IL-17RB, binds both IL-17B and IL-17E.<ref name="Kolls2004"/><ref name="Moseley2003"/> Furthermore, it is expressed in the kidney, pancreas, liver, brain, and intestine.<ref name="Kolls2004"/> 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.<ref name="Kolls2004"/><ref name="Moseley2003"/> The least-described of these receptors, IL-17RE, is known to be expressed in the pancreas, brain, and prostate.<ref name="Kolls2004"/>

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.<ref name="Kawaguchi2004"/> Transcription factors such as [[TRAF|TRAF6]], [[Janus kinase|JNK]], [[Erk kinase|Erk1/2]], p38, [[AP-1 transcription factor|AP-1]] and [[NF-κB]] have been implicated in IL-17 mediated signaling in a stimulation-dependent, tissue-specific manner.<ref name="Kawaguchi2004" /><ref name="Moseley2003"/><ref name="pmid16891673">{{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 }}</ref> Other signaling mechanisms have also been proposed, but more work is needed to fully elucidate the true signaling pathways used by these diverse receptors.

== References ==
{{Reflist|33em}}

{{Interleukins}}
{{Interleukin receptor modulators}}

[[Category:Interleukins]]

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Interleukin 17