Structure and function of interleukin-17 family cytokines

Abstract

The recently identified interleukin-17 (IL-17) cytokines family, which comprises six members in mammals (IL-17A-F), plays essential roles in the host immunity against infectious diseases and chronic inflammatory diseases. The three-dimensional structures containing IL-17A or IL-17F have become available and revealed the unique structural features of IL-17s as well as their receptors. Molecular modeling in this review shows that IL-17s may adopt a “cysteine knot” fold commonly seen in nerve growth factor (NGF) and other neurotrophins. Further modeling analysis unmasks a signature interaction feature of the IL-17F/IL-17RA complex, where a small loop of IL-17RA slots into the deep groove of the interface of IL-17F homodimer. This is quite different from the interaction between the best known four-helix cytokines and their cognate receptors. On the other hand, structure of IL-17A and its monoclonal antibody (CAT-2200) shows that, albeit that the antigenic epitope of IL-17A resides outside of the IL-17A homodimer interface, its physical proximity to the receptor binding groove may explain that antibody blockage would be achieved by interfering with the ligand-receptor interaction. This review is to summarize the advance in understanding the structure and function of IL-17 family cytokines, focusing mainly on IL-17A, IL-17F and IL-17E, in the hope of gaining better knowledge of immunotherapeutic strategies against various inflammatory diseases.

Keywords

interleukin-17 / cytokines / crystal structure / immunology

References

[1] Aggarwal, S., Ghilardi, N., Xie, M.H., de Sauvage, F.J., and Gurney, A.L. (2003). Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278, 1910-1914 .12417590
[2] Akimzhanov, A.M., Yang, X.O., and Dong, C. (2007). Chromatin remodeling of interleukin-17 (IL-17)-IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J Biol Chem 282, 5969-5972 .17218320
[3] Angkasekwinai, P., Chang, S.H., Thapa, M., Watarai, H., and Dong, C. (2010). Regulation of IL-9 expression by IL-25 signaling. Nat Immunol 11, 250-256 .20154671
[4] Angkasekwinai, P., Park, H., Wang, Y.H., Wang, Y.H., Chang, S.H., Corry, D.B., Liu, Y.J., Zhu, Z., and Dong, C. (2007). Interleukin 25 promotes the initiation of proallergic type 2 responses. J Exp Med 204, 1509-1517 .17562814
[5] Arend, W.P., Palmer, G., and Gabay, C. (2008). IL-1, IL-18, and IL-33 families of cytokines. Immunol Rev 223, 20-38 .18613828
[6] Awane, M., Andres, P.G., Li, D.J., and Reinecker, H.C. (1999). NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells. J Immunol 162, 5337-5344 .10228009
[7] Barksby, H.E., Lea, S.R., Preshaw, P.M., and Taylor, J.J. (2007). The expanding family of interleukin-1 cytokines and their role in destructive inflammatory disorders. Clin Exp Immunol 149, 217-225 .17590166
[8] Benatar, T., Cao, M.Y., Lee, Y., Li, H., Feng, N., Gu, X., Lee, V., Jin, H., Wang, M., Der, S., (2008). Virulizin induces production of IL-17E to enhance antitumor activity by recruitment of eosinophils into tumors. Cancer Immunol Immunother 57, 1757-1769 .18351336
[9] Benatar, T., Cao, M.Y., Lee, Y., Lightfoot, J., Feng, N., Gu, X., Lee, V., Jin, H., Wang, M., Wright, J.A., (2010). IL-17E, a proinflammatory cytokine, has antitumor efficacy against several tumor types in vivo. Cancer Immunol Immunother 59, 805-817 .20012860
[10] Bendtsen, J.D., Nielsen, H., von Heijne, G., and Brunak, S. (2004). Improved prediction of signal peptides: SignalP 3.0. J Mol Biol 340, 783-795 .15223320
[11] Boulanger, M.J., Chow, D.C., Brevnova, E.E., and Garcia, K.C. (2003). Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science 300, 2101-2104 .12829785
[12] Chabaud, M., Durand, J.M., Buchs, N., Fossiez, F., Page, G., Frappart, L., and Miossec, P. (1999). Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 42, 963-970 .10323452
[13] Chang, S.H., and Dong, C. (2007). A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell Res 17, 435-440 .17452998
[14] Chang, S.H., Park, H., and Dong, C. (2006). Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J Biol Chem 281, 35603-35607 .17035243
[15] Claudio, E., S?nder, S.U., Saret, S., Carvalho, G., Ramalingam, T.R., Wynn, T.A., Chariot, A., Garcia-Perganeda, A., Leonardi, A., Paun, A., (2009). The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation. J Immunol 182, 1617-1630 .19155511
[16] Curtis, M.M., and Way, S.S. (2009). Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology 126, 177-185 .19125888
[17] de Moura, P.R., Watanabe, L., Bleicher, L., Colau, D., Dumoutier, L., Lemaire, M.M., Renauld, J.C., and Polikarpov, I. (2009). Crystal structure of a soluble decoy receptor IL-22BP bound to interleukin-22. FEBS Lett 583, 1072-1077 .19285080
[18] Dinarello, C.A. (2009). Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27, 519-550 .19302047
[19] Dolgachev, V., Petersen, B.C., Budelsky, A.L., Berlin, A.A., and Lukacs, N.W. (2009). Pulmonary IL-17E (IL-25) production and IL-17RB+ myeloid cell-derived Th2 cytokine production are dependent upon stem cell factor-induced responses during chronic allergic pulmonary disease. J Immunol 183, 5705-5715 .19828636
[20] Ely, L.K., Fischer, S., and Garcia, K.C. (2009). Structural basis of receptor sharing by interleukin 17 cytokines. Nat Immunol 10, 1245-1251 .19838198
[21] Emamaullee, J.A., Davis, J., Merani, S., Toso, C., Elliott, J.F., Thiesen, A., and Shapiro, A.M. (2009). Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice. Diabetes 58, 1302-1311 .19289457
[22] Fort, M.M., Cheung, J., Yen, D., Li, J., Zurawski, S.M., Lo, S., Menon, S., Clifford, T., Hunte, B., Lesley, R., (2001). IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15, 985-995 .11754819
[23] Fossiez, F., Djossou, O., Chomarat, P., Flores-Romo, L., Ait-Yahia, S., Maat, C., Pin, J.J., Garrone, P., Garcia, E., Saeland, S., (1996). T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 183, 2593-2603 .8676080
[24] Gerhardt, S., Abbott, W.M., Hargreaves, D., Pauptit, R.A., Davies, R.A., Needham, M.R., Langham, C., Barker, W., Aziz, A., Snow, M.J., (2009). Structure of IL-17A in complex with a potent, fully human neutralizing antibody. J Mol Biol 394, 905-921 .19835883
[25] Gong, Y., Cao, P., Yu, H.J., and Jiang, T. (2008). Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex. Nature 454, 789-793 .18596692
[26] Goswami, S., Angkasekwinai, P., Shan, M., Greenlee, K.J., Barranco, W.T., Polikepahad, S., Seryshev, A., Song, L.Z., Redding, D., Singh, B., (2009). Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma. Nat Immunol 10, 496-503 .19329997
[27] Haudenschild, D., Moseley, T., Rose, L., and Reddi, A.H. (2002). Soluble and transmembrane isoforms of novel interleukin-17 receptor-like protein by RNA splicing and expression in prostate cancer. J Biol Chem 277, 4309-4316 .11706037
[28] Hymowitz, S.G., Filvaroff, E.H., Yin, J.P., Lee, J., Cai, L., Risser, P., Maruoka, M., Mao, W., Foster, J., Kelley, R.F., (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 .11574464
[29] Ikeda, K., Nakajima, H., Suzuki, K., Kagami, S., Hirose, K., Suto, A., Saito, Y., and Iwamoto, I. (2003). Mast cells produce interleukin-25 upon Fc epsilon RI-mediated activation. Blood 101, 3594-3596 .12511410
[30] Ishigame, H., Kakuta, S., Nagai, T., Kadoki, M., Nambu, A., Komiyama, Y., Fujikado, N., Tanahashi, Y., Akitsu, A., Kotaki, H., (2009). Differential roles of interleukin-17A and-17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30, 108-119 .19144317
[31] Ivanov, I.I., McKenzie, B.S., Zhou, L., Tadokoro, C.E., Lepelley, A., Lafaille, J.J., Cua, D.J., and Littman, D.R. (2006). The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121-1133 .16990136
[32] Kang, C.M., Jang, A.S., Ahn, M.H., Shin, J.A., Kim, J.H., Choi, Y.S., Rhim, T.Y., and Park, C.S. (2005). Interleukin-25 and interleukin-13 production by alveolar macrophages in response to particles. Am J Respir Cell Mol Biol 33, 290-296 .15961726
[33] Kawaguchi, M., Kokubu, F., Odaka, M., Watanabe, S., Suzuki, S., Ieki, K., Matsukura, S., Kurokawa, M., Adachi, M., and Huang, S.K. (2004). Induction of granulocyte-macrophage colony-stimulating factor by a new cytokine, ML-1 (IL-17F), via Raf I-MEK-ERK pathway. J Allergy Clin Immunol 114, 444-450 .15316530
[34] Kim, M.R., Manoukian, R., Yeh, R., Silbiger, S.M., Danilenko, D.M., Scully, S., Sun, J., DeRose, M.L., Stolina, M., Chang, D., (2002). Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production. Blood 100, 2330-2340 .12239140
[35] Kleinschek, M.A., Owyang, A.M., Joyce-Shaikh, B., Langrish, C.L., Chen, Y., Gorman, D.M., Blumenschein, W.M., McClanahan, T., Brombacher, F., Hurst, S.D., (2007). IL-25 regulates Th17 function in autoimmune inflammation. J Exp Med 204, 161-170 .17200411
[36] Kolls, J.K., and Lindén, A. (2004). Interleukin-17 family members and inflammation. Immunity 21, 467-476 .15485625
[37] Kuestner, R.E., Taft, D.W., Haran, A., Brandt, C.S., Brender, T., Lum, K., Harder, B., Okada, S., Ostrander, C.D., Kreindler, J.L., (2007). Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. J Immunol 179, 5462-5473 .17911633
[38] Kurasawa, K., Hirose, K., Sano, H., Endo, H., Shinkai, H., Nawata, Y., Takabayashi, K., and Iwamoto, I. (2000). Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum 43, 2455-2463 .11083268
[39] Lee, J., Ho, W.H., Maruoka, M., Corpuz, R.T., Baldwin, D.T., Foster, J.S., Goddard, A.D., Yansura, D.G., Vandlen, R.L., Wood, W.I., (2001). IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J Biol Chem 276, 1660-1664 .11058597
[40] Leonardi, A., Chariot, A., Claudio, E., Cunningham, K., and Siebenlist, U. (2000). CIKS, a connection to Ikappa B kinase and stress-activated protein kinase. Proc Natl Acad Sci U S A 97, 10494-10499 .10962033
[41] Li, H., Chen, J., Huang, A., Stinson, J., Heldens, S., Foster, J., Dowd, P., Gurney, A.L., and Wood, W.I. (2000a). Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc Natl Acad Sci U S A 97, 773-778 .10639155
[42] Li, X., Commane, M., Nie, H., Hua, X., Chatterjee-Kishore, M., Wald, D., Haag, M., and Stark, G.R. (2000b). Act1, an NF-kappa B-activating protein. Proc Natl Acad Sci U S A 97, 10489-10493 .10962024
[43] Liang, S.C., Long, A.J., Bennett, F., Whitters, M.J., Karim, R., Collins, M., Goldman, S.J., Dunussi-Joannopoulos, K., Williams, C.M., Wright, J.F., (2007). An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment. J Immunol 179, 7791-7799 .18025225
[44] Lindén, A. (2007). A role for the cytoplasmic adaptor protein Act1 in mediating IL-17 signaling. Sci STKE 2007, re4.17684298
[45] Lingel, A., Weiss, T.M., Niebuhr, M., Pan, B., Appleton, B.A., Wiesmann, C., Bazan, J.F., and Fairbrother, W.J. (2009). Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors—insight into heterotrimeric IL-1 signaling complexes. Structure 17, 1398-1410 .19836339
[46] McDonald, N.Q., and Hendrickson, W.A. (1993). A structural superfamily of growth factors containing a cystine knot motif. Cell 73, 421-424 .8490958
[47] McElroy, C.A., Dohm, J.A., and Walsh, S.T. (2009). Structural and biophysical studies of the human IL-7/IL-7Ralpha complex. Structure 17, 54-65 .19141282
[48] Moseley, T.A., Haudenschild, D.R., Rose, L., and Reddi, A.H. (2003). Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14, 155-174 .12651226
[49] Nicola, N.A., and Hilton, D.J. (1998). General classes and functions of four-helix bundle cytokines. Adv Protein Chem 52, 1-65 .9917917
[50] Novatchkova, M., Leibbrandt, A., Werzowa, J., Neubüser, A., and Eisenhaber, F. (2003). The STIR-domain superfamily in signal transduction, development and immunity. Trends Biochem Sci 28, 226-229 .12765832
[51] Oda, N., Canelos, P.B., Essayan, D.M., Plunkett, B.A., Myers, A.C., and Huang, S.K. (2005). Interleukin-17F induces pulmonary neutrophilia and amplifies antigen-induced allergic response. Am J Respir Crit Care Med 171, 12-18 .15477493
[52] Pan, G., French, D., Mao, W., Maruoka, M., Risser, P., Lee, J., Foster, J., Aggarwal, S., Nicholes, K., Guillet, S., (2001). Forced expression of murine IL-17E induces growth retardation, jaundice, a Th2-biased response, and multiorgan inflammation in mice. J Immunol 167, 6559-6567 .11714825
[53] Park, H., Li, Z., Yang, X.O., Chang, S.H., Nurieva, R., Wang, Y.H., Wang, Y., Hood, L., Zhu, Z., Tian, Q., (2005). A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6, 1133-1141 .16200068
[54] Pollastri, G., and McLysaght, A. (2005). Porter: a new, accurate server for protein secondary structure prediction. Bioinformatics 21, 1719-1720 .15585524
[55] Qian, Y., Liu, C., Hartupee, J., Altuntas, C.Z., Gulen, M.F., Jane-Wit, D., Xiao, J., Lu, Y., Giltiay, N., Liu, J., (2007). The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol 8, 247-256 .17277779
[56] Rickel, E.A., Siegel, L.A., Yoon, B.R., Rottman, J.B., Kugler, D.G., Swart, D.A., Anders, P.M., Tocker, J.E., Comeau, M.R., and Budelsky, A.L. (2008). Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J Immunol 181, 4299-4310 .18768888
[57] Schwandner, R., Yamaguchi, K., and Cao, Z. (2000). Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J Exp Med 191, 1233-1240 .10748240
[58] Shalom-Barak, T., Quach, J., and Lotz, M. (1998). Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF-kappaB. J Biol Chem 273, 27467-27473 .9765276
[59] Shi, Y., Ullrich, S.J., Zhang, J., Connolly, K., Grzegorzewski, K.J., Barber, M.C., Wang, W., Wathen, K., Hodge, V., Fisher, C.L., (2000). A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity. J Biol Chem 275, 19167-19176 .10749887
[60] Sonobe, Y., Takeuchi, H., Kataoka, K., Li, H., Jin, S., Mimuro, M., Hashizume, Y., Sano, Y., Kanda, T., Mizuno, T., (2009). Interleukin-25 expressed by brain capillary endothelial cells maintains blood-brain barrier function in a protein kinase Cepsilon-dependent manner. J Biol Chem 284, 31834-31842 .19776017
[61] Starnes, T., Broxmeyer, H.E., Robertson, M.J., and Hromas, R. (2002). Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis. J Immunol 169, 642-646 .12097364
[62] Starnes, T., Robertson, M.J., Sledge, G., Kelich, S., Nakshatri, H., Broxmeyer, H.E., and Hromas, R. (2001). Cutting edge: IL-17F, a novel cytokine selectively expressed in activated T cells and monocytes, regulates angiogenesis and endothelial cell cytokine production. J Immunol 167, 4137-4140 .11591732
[63] Swaidani, S., Bulek, K., Kang, Z., Liu, C., Lu, Y., Yin, W., Aronica, M., and Li, X. (2009). The critical role of epithelial-derived Act1 in IL-17- and IL-25-mediated pulmonary inflammation. J Immunol 182, 1631-1640 .19155512
[64] Terashima, A., Watarai, H., Inoue, S., Sekine, E., Nakagawa, R., Hase, K., Iwamura, C., Nakajima, H., Nakayama, T., and Taniguchi, M. (2008). A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity. J Exp Med 205, 2727-2733 .19015310
[65] Teunissen, M.B., Koomen, C.W., de Waal Malefyt, R., Wierenga, E.A., and Bos, J.D. (1998). Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J Invest Dermatol 111, 645-649 .9764847
[66] Tian, E., Sawyer, J.R., Largaespada, D.A., Jenkins, N.A., Copeland, N.G., and Shaughnessy, J.D. Jr. (2000). Evi27 encodes a novel membrane protein with homology to the IL17 receptor. Oncogene 19, 2098-2109 .10815801
[67] Toy, D., Kugler, D., Wolfson, M., Vanden Bos, T., Gurgel, J., Derry, J., Tocker, J., and Peschon, J. (2006). Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol 177, 36-39 .16785495
[68] Vigers, G.P., Anderson, L.J., Caffes, P., and Brandhuber, B.J. (1997). Crystal structure of the type-I interleukin-1 receptor complexed with interleukin-1beta. Nature 386, 190-194 .9062193
[69] Wang, X., Lupardus, P., Laporte, S.L., and Garcia, K.C. (2009). Structural biology of shared cytokine receptors. Annu Rev Immunol 27, 29-60 .18817510
[70] Wang, Y.H., Angkasekwinai, P., Lu, N., Voo, K.S., Arima, K., Hanabuchi, S., Hippe, A., Corrigan, C.J., Dong, C., Homey, B., (2007). IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J Exp Med 204, 1837-1847 .17635955
[71] Wright, J.F., Bennett, F., Li, B., Brooks, J., Luxenberg, D.P., Whitters, M.J., Tomkinson, K.N., Fitz, L.J., Wolfman, N.M., Collins, M., (2008). The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J Immunol 181, 2799-2805 .18684971
[72] Wright, J.F., Guo, Y., Quazi, A., Luxenberg, D.P., Bennett, F., Ross, J.F., Qiu, Y., Whitters, M.J., Tomkinson, K.N., Dunussi-Joannopoulos, K., (2007). Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells. J Biol Chem 282, 13447-13455 .17355969
[73] Yang, X.O., Chang, S.H., Park, H., Nurieva, R., Shah, B., Acero, L., Wang, Y.H., Schluns, K.S., Broaddus, R.R., Zhu, Z., (2008). Regulation of inflammatory responses by IL-17F. J Exp Med 205, 1063-1075 .18411338
[74] Yao, Z., Fanslow, W.C., Seldin, M.F., Rousseau, A.M., Painter, S.L., Comeau, M.R., Cohen, J.I., and Spriggs, M.K. (1995a). Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3, 811-821 .8777726
[75] Yao, Z., Painter, S.L., Fanslow, W.C., Ulrich, D., Macduff, B.M., Spriggs, M.K., and Armitage, R.J. (1995b). Human IL-17: a novel cytokine derived from T cells. J Immunol 155, 5483-5486 .7499828
[76] Yao, Z., Spriggs, M.K., Derry, J.M., Strockbine, L., Park, L.S., VandenBos, T., Zappone, J.D., Painter, S.L., and Armitage, R.J. (1997). Molecular characterization of the human interleukin (IL)-17 receptor. Cytokine 9, 794-800 .9367539
[77] Zaph, C., Du, Y., Saenz, S.A., Nair, M.G., Perrigoue, J.G., Taylor, B.C., Troy, A.E., Kobuley, D.E., Kastelein, R.A., Cua, D.J., (2008). Commensal-dependent expression of IL-25 regulates the IL-23-IL-17 axis in the intestine. J Exp Med 205, 2191-2198 .18762568s