IL-17 - rs.tus.ac.jp

1 1 IL-17 -17A interleukin-17A: IL-17A 21kDa 1993 T 1995 IL-17A IL-17 IL-17A 63% IL-17B IL-17C IL-17D IL-17E IL-25 IL-17F IL-17 1 IL-17A IL-6 - tumor necrosis factor- : TNF- IL-17 T - interferon- : IFN- Th1 IL-4 Th2 CD4+T IL-17A CD4+T Th17 1 IL-17A RA 2 IL-17A IL-17F IL-17 IL-17A IL-17F 50% Th17 1 IL-17A IL-17F IL-17A IL-17F IL-1 IL-6 TNF- CXCL1 MMP matrix metalloproteinase 1 2 IL-17A G-CSF granulocyte-colony stimulating factor CXCL8 IL-8 IL-17F IL-17A 3 2 IL-17A IL-17F T Th17

2 Th17 IL-17A IL-17F IL-21 IL-22 TGF- IL-6 IL-21 CD4 T IL-1 IL-23 IL-6 IL-21 IL-23 STAT3 Th17 ROR t retinoic acid receptor-related orphan receptor- t Th17 Th17 Th17 IL-1 IL-6 Th17 TGF- Th17 Th17 3 2008 Th17 TGF- 4 Th17 Th17 IL-17A IL-17F CD8+T T NKT T lymphoid tissue inducer (LTi)-like NK 4 IL-17A IL-17F 1 2 RA IL-17A 5 IL-17A IL-17F 2 Th17 IL-17A IL-17F Th17 IL-17A IL-17F IL-17 IL-17RA IL-17RB IL-17RC IL-17RD IL-17RE FnIII III IL-1/Toll-like receptor TIR Toll/IL-1R SEFIR Similar expression to fibroblast growth factor/IL-17R IL-17 IL-17A IL-17F IL-17RA IL-17RC 1 3 IL-17A IL-17F NF- B MAPK C/EBP Act1 SEFIR TRAF6 TAK1 5 IL-17A

3 IL-17F RA IFN- Th1 IL-12 p40 Th1 RA CIA IL-12 p35 IFN- Th1 2003 p19 IL-23 p40 IL-12/IL-23 CIA p35 IL-12 6 p19 T IFN- IL-17A p35 IFN- IL-17A IL-17A CIA IL-17A CIA 7 CIA IL-12 IL-23 CIA Th1 Th17 HTLV-I human T-cell leukemia virus-I IL-1 Ra 8 IL-17 9, 6 10 4 IL-6 gp130 F759 gp130 STAT3 IL-17A 11 TCR ZAP-70 SKG IL-17A 12 IL-17A IL-17F IL-17A/F IL-17A/F IL-1Ra IL-17F CIA IL-17F 2 5 IL-17A IL-17F IL-17A IL-17A RA IL-17A 7 T Th17 13 IL-17A RA Th17 IL-17 IL-6 Tocilizumab 2008 RA

4 Th17 IL-17A LY2439821 RA 14 IL-17A IL-17F IL-17A RA IL-17A EAE IL-17A 2 IL-17A EAE IL-23 IL-17A 15 IL-17A Th17 T 16 DTH CHS IV IL-17A 17 IL-17A IL-17F CIA EAE DTH CHS IL-17F 2 Staphylococcus aureus Citrobacter rodentium IL-17A IL-17F 2 IL-17A IL-17F 8 IL-17E IL-17E IL-17 IL-17A 16% IL-17A IL-17F Th17 Th2 IL-17E IL-17RA IL-17RB IL-17E NF- B MAPK C/EBP 3 IL-17E Th2 IL-4 IL-5 IL-13 Th2 IgE L-17E IL-17E Th2 T IL-5 IL-13 Th2 IL-17E NH multiple potent progenitor type 2 MMPtype2 nuocyte innate type2 helper Ih2 6 18 IL-17E IL-17A EAE IL-17A IL-17E IL-13

5 IL-17E Th17 9 19 IL-17E EAE CIA IL-17E IL-4 20 IL-4 Th17 IL-17E IL-17C IL-17C CIA CD4+T TNF- IL-1 21 IL-17C CD4+T CIA 22 IL-17C IL-17RA IL-17RE Act1 23 IL-17C NF- B MAPK 24 IL-17C IL-17A TNF- IL-1 IL-17C IL-17C 24, 25 IL-17C Th17 IL-17A EAE 23 IL-17C EAE IL-17B IL-17D IL-17B CIA IL-17C TNF- IL-1 21 IL-17B CD4+T CIA IL-17B CIA 22 IL-17B IL-17RB IL-17D CD4+T B 26 IL-17D IL-6 IL-8 10 GM-CSF RA 27 IL-17D IL-17B IL-17D IL-17A IL-17F IL-17C IL-1 IL-6 TNF-a RA IL-17A RA

6 IL-1 IL-6 TNF-a IL-17A IL-17F IL-17A IL-17 RA 11 1. Iwakura, Y., Ishigame, H., Saijo, S. & Nakae, S. Functional specialization of interleukin-17 family members. Immunity 34, 149-162 (2011). 2. Ishigame, H. et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30, 108-119 (2009). 3. Acosta-Rodriguez, , Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.

7 Nat Immunol 8, 942-949 (2007). 4. Yang, L. et al. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454, 350-352 (2008). 5. Hueber, et al. Mast cells express IL-17A in rheumatoid arthritis synovium. J Immunol 184, 3336-3340 (2010). 6. Murphy, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198, 1951-1957 (2003). 7. Nakae, S., Nambu, A., Sudo, K. & Iwakura, Y. Suppression of immune induction of collagen-induced arthritis in IL-17 -deficient mice. J Immunol 171, 6173-6177 (2003). 8. Iwakura, Y. Roles of IL-1 in the development of rheumatoid arthritis: consideration from mouse models. Cytokine Growth Factor Rev 13, 341-355 (2002). 9. Iwakura, Y., Nakae, S., Saijo, S. & Ishigame, H.

8 The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev 226, 57-79 (2008). 10. Nakae, S. et al. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci U S A 100, 5986-5990 (2003). 11. Ogura, H. et al. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity 29, 12 628-636 (2008). 12. Hirota, K. et al. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17 + Th cells that cause autoimmune arthritis. J Exp Med 204, 41-47 (2007). 13. Sato, K. et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction.

9 The Journal of experimental medicine 203, 2673-2682 (2006). 14. Genovese, et al. LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum 62, 929-939 (2010). 15. Rizzo, et al. IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A. J Immunol 186, 1495-1502 (2011). 16. Cai, Y. et al. Pivotal role of dermal IL-17 -producing gammadelta T cells in skin inflammation. Immunity 35, 596-610 (2011). 17. Nakae, S. et al. Antigen-specific T cell sensitization is impaired in IL-17 -deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375-387 (2002). 18.

10 Saenz, , Noti, M. & Artis, D. Innate immune cell populations function as initiators and effectors in Th2 cytokine responses. Trends Immunol 31, 407-413 (2010). 19. Kleinschek, et al. IL-25 regulates Th17 function in autoimmune inflammation. J Exp Med 204, 161-170 (2007). 20. Kaiwen, W. et al. Changes and significance of IL-25 in chicken collagen II-induced experimental arthritis (CIA). Rheumatology international (2011). 21. Li, H. et al. 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 (2000). 22. Yamaguchi, Y. et al. IL-17B and IL-17C are associated with TNF-alpha production and contribute to the exacerbation of inflammatory arthritis. J Immunol 179, 7128-7136 (2007).