Interleukin 17

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Interleukin 17
Identifiers
Symbol(s)	IL17 , IL17A, CTLA8
Entrez	3605
OMIM	603149
RefSeq	NP_002181
UniProt	U32659
Other data
Locus	Chr. 2 q31

Interleukin 17B
Identifiers
Symbol(s)	IL17B , ZCOTO7
Entrez	27190
OMIM	604627
RefSeq	NP_055258
UniProt	Q9UHF5
Other data
Locus	Chr. 5 q32-34

Interleukin 17C
Identifiers
Symbol(s)	IL17C , CX2
Entrez	271989
OMIM	604628
RefSeq	NP_037410
UniProt	Q9P0M4
Other data
Locus	Chr. 16 q24

Interleukin 17D
Identifiers
Symbol(s)	IL17D
Entrez	53342
OMIM	607587
RefSeq	NP_612141
UniProt	Q8TAD2
Other data
Locus	Chr. 13 q11

Interleukin 17E
Identifiers
Symbol(s)	IL17E , IL-25
Entrez	64806
OMIM	605658
RefSeq	NP_073626
UniProt	Q9H293
Other data
Locus	Chr. 14 q11.2

Interleukin 17F
Identifiers
Symbol(s)	IL17F , ML-1
Entrez	112744
OMIM	606496
RefSeq	NP_443104
UniProt	Q96PD4
Other data
Locus	Chr. 6 p12

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.^[2]

Contents 1 Members of the IL-17 family 2 Functions of the IL-17 family 3 Gene expression of the IL-17 family 4 Regulation of IL-17 Expression 5 Protein Structure of IL-17 Family 6 IL-17 Receptor Family Distribution and Signaling 7 References

[edit] 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]

[edit] 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]

[edit] 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]

[edit] 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, RORγt, directs differentiation of IL-17-producing T cells.^[12]

[edit] 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.^[13].

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.^[14].

[edit] IL-17 Receptor Family Distribution and Signaling

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][15][16].

Another member of this receptor family, IL-17RB, binds both IL-17B and IL-17E^[3][16]. 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][16]. 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^[15]. 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^[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.

[edit] References

1. ^ Rouvier, E., Luciani, M.F., Mattei, M.G., Denizot, F. & Golstein, P. 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, 5445-56 (1993)
2. ^ Starnes T., et al., IL-17D, a Novel Member of the IL-17 Family, Stimulates Cytokine Production and Inhibits Hemopoiesis., Journal of Immunology, 2002, Volume 169, pages 642-646.
3. ^ ^{a b c d e f g} Kolls, J.K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467-76 (2004).
4. ^ ^{a b} Aggarwal and Gurney, IL-17: prototype member of an emerging cytokine family. Journal of Leukococyte Biology, 2002, Volume 71, pages 1–8.
5. ^ ^{a b} Yao, Z., S.L. Painter, W.C. Fanslow, D. Ulrich, B.M. Macduff, M.K. Spriggs, and R.J. Armitage. 1995. Human IL-17: a novel cytokine derived from T cells. J Immunol 155:5483-5486.
6. ^ Aggarwal, S., N. Ghilardi, M.H. Xie, F.J. de Sauvage, and A.L. Gurney. 2003. IL-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278:1910-1914.
7. ^ Cho, M.L., J.W. Kang, Y.M. Moon, H.J. Nam, J.Y. Jhun, S.B. Heo, H.T. Jin, S.Y. Min, J.H. Ju, K.S. Park, Y.G. Cho, C.H. Yoon, S.H. Park, Y.C. Sung, and H.Y. Kim. 2006. STAT3 and NF-κB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J Immunol 176:5652-5661.
8. ^ Chen, Z., A. Laurence, Y. Kanno, M. Pacher-Zavisin, B.M. Zhu, C. Tato, A. Yoshimura, L. Hennighausen, and J.J. O'Shea. 2006. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci U S A 103:8137-8142.
9. ^ ^{a b} Veldhoen, M., R.J. Hocking, C.J. Atkins, R.M. Locksley, and B. Stockinger. 2006. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179-189
10. ^ ^{a b} Mangan, P.R., L.E. Harrington, D.B. O'Quinn, W.S. Helms, D.C. Bullard, C.O. Elson, R.D. Hatton, S.M. Wahl, T.R. Schoeb, and C.T. Weaver. 2006. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231-234.
11. ^ ^{a b} Bettelli, E., Y. Carrier, W. Gao, T. Korn, T.B. Strom, M. Oukka, H.L. Weiner, and V.K. Kuchroo. 2006. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235-238.
12. ^ 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 RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121-1133.
13. ^ Aggarwal, S., and A.L. Gurney. 2002. IL-17: prototype member of an emerging cytokine family. J Leukoc Biol 71:1-8.
14. ^ Hymowitz, S.G., E.H. Filvaroff, J.P. Yin, J. Lee, L. Cai, P. Risser, M. Maruoka, W. Mao, J. Foster, R.F. Kelley, G. Pan, A.L. Gurney, A.M. de Vos, and M.A. Starovasnik. 2001. IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. Embo J 20:5332-5341.
15. ^ ^{a b c} Kawaguchi M., Adachi M., Oda N., Kokubu F., Huang S., 2004. IL-17 cytokine family. J Allergy Clin Immunol 114(6):1265-1273.
16. ^ ^{a b c d} Moseley T.A., Haudenschild D.R., Rose L. and Reddi A.H. 2003. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Reviews. 14:155-174.