title: A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis.
abstract: It was recently demonstrated that interleukin (IL)-23-driven IL-17-producing (ThIL-17) T cells mediate inflammatory pathology in certain autoimmune diseases. We show that the induction of antigen-specific ThIL-17 cells, but not T helper (Th)1 or Th2 cells, by immunization with antigens and adjuvants is abrogated in IL-1 receptor type I-deficient (IL-1RI(-/-)) mice. Furthermore, the incidence of experimental autoimmune encephalomyelitis (EAE) was significantly lower in IL-1RI(-/-) compared with wild-type mice, and this correlated with a failure to induce autoantigen-specific ThIL-17 cells, whereas induction of Th1 and Th2 responses was not substantially different. However, EAE was induced in IL-1RI(-/-) mice by adoptive transfer of autoantigen-specific cells from wild-type mice with EAE. IL-23 alone did not induce IL-17 production by T cells from IL-1RI(-/-) mice, and IL-23-induced IL-17 production was substantially enhanced by IL-1alpha or IL-1beta, even in the absence of T cell receptor stimulation. We demonstrate essential roles for phosphatidylinositol 3-kinase, nuclear factor kappaB, and novel protein kinase C isoforms in IL-1- and IL-23-mediated IL-17 production. Tumor necrosis factor alpha also synergized with IL-23 to enhance IL-17 production, and this was IL-1 dependent. Our findings demonstrate that IL-1 functions upstream of IL-17 to promote pathogenic ThIL-17 cells in EAE.
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sutton
authors.forename: Corinna
authors.initials: C
authors.lastname: Brereton
authors.forename: Brian
authors.initials: B
authors.lastname: Keogh
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D007113:Immunity, Innate / Q000235:genetics; D007375:Interleukin-1 / Q000502:physiology*; D020381:Interleukin-17 / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D053573:Receptors, Interleukin-1 Type I; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D007375:Interleukin-1; D020381:Interleukin-17; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I