82 : IL-36 promotes myeloid cell infiltration, activation and inflammatory activity in skin

The IL-1 family members IL-36 α (IL-1F6), IL-36 β (IL-1F8) and IL-36 γ (IL-1F9) and the receptor antagonist IL-36Ra (IL-1F5) constitute a novel signaling system that is poorly understood. We now show that these cytokines have profound effects on the skin immune system. Treatment of human keratinocytes with IL-36 α or IL-36 β significantly increased the expression of CXCL1, CCL5, CCL20, CXCL10 and CCL22, potent chemotactic agents for activated leukocytes, and IL-36 α injected intradermally resulted in chemokine expression, leukocyte infiltration and acanthosis of mouse skin. Blood monocytes, myeloid dendritic cells (DC) and monocyte-derived DC (MO-DC) expressed IL-36R and responded to IL-36. In contrast, no direct effects of IL-36 on resting or activated human CD4+ or CD8+ T cells, or blood neutrophils, could be demonstrated. Monocytes expressed IL-1A, IL-1B and IL-6 mRNA and IL-1 β and IL-6 protein and mDC upregulated surface expression of CD83, CD86 and HLA-DR and secretion of IL-1 β and IL-6 after treatment with IL-36. Furthermore, IL-36 α -treated MO-DC enhanced allogeneic CD4+ T cell proliferation, demonstrating that IL-36 can stimulate the maturation and function of DC and drive T cell proliferation. These data indicate that IL-36 cytokines actively propagate skin inflammation via the activation of keratinocytes, antigen presenting cells and, indirectly, T cells.