Interleukin 17
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Interleukin-17 (IL-17, or IL-17A) is the founding member of a group of cytokines called the IL-17 family. IL-17A, was originally identified as a transcript from a rodent T-cell hybridoma by Rouvier et al. in 1993. Known as CTLA8 in rodents, IL-17 shows high homology to viral IL-17 encoded by an open reading frame of the T lymphotropic rhadinovirus Herpesvirus saimiri.[1] To elicit its functions, IL-17 binds to a type I cell surface receptor called IL-17R of which there are at least three variants IL17RA, IL17RB, and IL17RC.[2]
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Members of the IL-17 family
In addition to IL-17A, members of the IL-17 family include IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F. All members of the IL-17 family have a similar protein structure, with four highly conserved cysteine residues critical to their 3-dimensional shape yet they have no sequence similarity to any other known cytokines. Phylogenetic analysis reveals that among IL-17 family members, the IL-17F isoforms 1 and 2 (ML-1) have the highest homology to IL-17A (sharing 55 and 40% amino acid identity to IL-17A respectively), followed by IL-17B (29%), IL-17D (25%), IL-17C (23%), and IL-17E being most distantly related to IL-17A (17%). These cytokines are all well conserved in mammals, with as much as 62–88% of amino acids conserved between the human and mouse homologs.[3]
Functions of the IL-17 family
Numerous immune regulatory functions have been reported for the IL-17 family of cytokines, presumably due to their induction of many immune signaling molecules. Most notably, IL-17 is involved 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). 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 (Th17) 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, allograft rejection and anti-tumour immunity.[4]
Gene expression of the IL-17 family
The gene for human IL-17 is 1874 base pairs long[5] 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.[4]
Regulation of IL-17 Expression
Much progress has been made in the understanding of the regulation of IL-17. Initially, Aggarwal et al. showed that production of IL-17 was dependent on IL-23.[6] Later, a Korean group discovered that STAT3 and NF-κB signalling pathways are required for this IL-23-mediated IL-17 production.[7] Consistent with this finding, Chen et al. showed that another molecule, SOCS3, plays an important role in IL-17 production.[8] 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 groups have identified ways to induce IL-17 production both in vitro[9] and in vivo[10][11] by distinct cytokines, called TGF-β and IL-6, without the need for IL-23.[9][10][11] 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.[12]
Protein Structure of IL-17 Family
IL-17(A) is a 155 amino acid protein that is a disulfide linked, homodimeric, secreted glycoprotein with a molecular mass of 35kDa.[3] 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.[5] 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.[4]
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 neurotrophins. The cysteine knot fold is characterized by two sets of paired β-strands 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.[13]
IL-17 Receptor Family Distribution and Signaling
See also Interleukin-17 receptors.
The IL-17 receptor family consists of five, broadly distributed receptors that present with individual ligand specificities. Within this family of receptors, IL-17R is the best described. IL-17R 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.[3][14][15]
Another member of this receptor family, IL-17RB, binds both IL-17B and IL-17E.[3][15] Furthermore, it is expressed in the kidney, pancreas, liver, brain and intestine.[3] 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. Similarly, 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 as yet undefined ligands.[3][15] The least described of these receptors, IL-17RE, is known to be expressed in the pancreas, brain and prostate.[3]
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.[14] 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.[14][15][16] 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
- ^ Rouvier E, Luciani MF, Mattéi MG, Denizot F, Golstein P (1993). "CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene". J. Immunol. 150 (12): 5445–56. PMID 8390535. http://www.jimmunol.org/cgi/content/abstract/150/12/5445.
- ^ Starnes T, Broxmeyer HE, Robertson MJ, Hromas R (2002). "Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis". J. Immunol. 169 (2): 642–6. PMID 12097364. http://www.jimmunol.org/cgi/content/abstract/169/2/642.
- ^ a b c d e f g Kolls JK, Lindén A (2004). [Expression error: Missing operand for > "Interleukin-17 family members and inflammation"]. Immunity 21 (4): 467–76. doi:. PMID 15485625.
- ^ a b c Aggarwal S, Gurney AL (2002). "IL-17: prototype member of an emerging cytokine family". J. Leukoc. Biol. 71 (1): 1–8. PMID 11781375. http://www.jleukbio.org/cgi/content/abstract/71/1/1.
- ^ a b Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Spriggs MK, Armitage RJ (1995). "Human IL-17: a novel cytokine derived from T cells". J. Immunol. 155 (12): 5483–6. PMID 7499828. http://www.jimmunol.org/cgi/content/abstract/155/12/5483.
- ^ Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL (2003). [Expression error: Missing operand for > "Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17"]. J. Biol. Chem. 278 (3): 1910–4. doi:. PMID 12417590.
- ^ 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 (2006). "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". J. Immunol. 176 (9): 5652–61. PMID 16622035. http://www.jimmunol.org/cgi/content/abstract/176/9/5652.
- ^ Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O'Shea JJ (2006). [Expression error: Missing operand for > "Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells"]. Proc. Natl. Acad. Sci. U.S.A. 103 (21): 8137–42. doi:. PMID 16698929.
- ^ a b Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006). [Expression error: Missing operand for > "TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells"]. Immunity 24 (2): 179–89. doi:. PMID 16473830.
- ^ a b Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006). [Expression error: Missing operand for > "Transforming growth factor-beta induces development of the T(H)17 lineage"]. Nature 441 (7090): 231–4. doi:. PMID 16648837.
- ^ a b Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006). [Expression error: Missing operand for > "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells"]. Nature 441 (7090): 235–8. doi:. PMID 16648838.
- ^ Ivanov, II, B.S. McKenzie, L. Zhou, C.E. Tadokoro, A. Lepelley, J.J. Lafaille, D.J. Cua, and D.R. Littman. 2006. The orphan nuclear receptor ROR-γ directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121-1133.
- ^ 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 (2001). [Expression error: Missing operand for > "IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding"]. EMBO J. 20 (19): 5332–41. doi:. PMID 11574464.
- ^ a b c Kawaguchi M, Adachi M, Oda N, Kokubu F, Huang SK (2004). [Expression error: Missing operand for > "IL-17 cytokine family"]. J. Allergy Clin. Immunol. 114 (6): 1265–73; quiz 1274. doi:. PMID 15577820.
- ^ a b c d Moseley TA, Haudenschild DR, Rose L, Reddi AH (2003). [Expression error: Missing operand for > "Interleukin-17 family and IL-17 receptors"]. Cytokine Growth Factor Rev. 14 (2): 155–74. doi:. PMID 12651226.
- ^ Ley K, Smith E, Stark MA (2006). [Expression error: Missing operand for > "IL-17A-producing neutrophil-regulatory Tn lymphocytes"]. Immunol. Res. 34 (3): 229–42. doi:. PMID 16891673.
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