I08 IL-36 stimulates Th1 responses and is implicated in human psoriasis

Abstract

IL-36 α , IL-36 β , IL-36 γ and their antagonist IL-36Ra are members of the IL-1 family which are expressed in skin, airway, upper GI tract and other epithelial tissues. Elevated expression of IL-36 has been strongly linked to human plaque psoriasis based on the following evidence: (a) IL-36 α and IL-36 γ are dramatically upregulated in the lesional skin of psoriasis patients; (b) transgenic over-expression of IL-36 α in mouse skin results in an inflammatory condition strongly resembling psoriasis; and (c) human lesional skin transplanted onto an immunodeficient mouse is largely normalized by an anti-human IL-36R antibody. Interestingly, humans suffering from a psoriasis variant, generalized pustular psoriasis, have been shown to carry homozygous loss-of-function mutations in IL-36Ra. Because T cells are important in the pathology of psoriasis, we have begun to explore the effects of IL-36 on T cell function. IL-36R is highly expressed in nai¨ve Th0 cells, but not in Th1, Th2 or Th17 helper T cell subsets. Stimulation of activated Th0 cells with IL-36 leads to proliferation and IL-2 production but not to induction of polarized T cell cytokines. However, incubation of activated Th0 cells and bone marrow-derived dendritic cells with IL-36 results in substantial IFN γ production. The critical role of dendritic cells is to provide IL-12 to the T cells, and the combination of IL-12 and IL-36 leads to three times stronger production of IFN γ than does the combination of IL-12 and IL-18. This response is also relevant in vivo , since IL-36R -/- mice infected with Mycobacterium Calmette-Guerin generate weaker IFN γ responses and show more pathology than similarly-infected wild-type mice.