Interleukin-36 (IL-36) is the common name for the three IL-1 family members IL-36α, IL-36β and IL-36γ, formerly known as IL-1F6, IL-1F8 and IL-1F9, respectively. IL-36 appears to have pro-inflammatory activities; however, the physiological function of these cytokines remains unknown. Expression of IL-36 by keratinocytes implies its possible involvement in innate immune responses in the skin. We observed that, of the three IL-36 isoforms, human keratinocytes express high levels of IL-36γ. IL-36γ mRNA expression was dramatically induced by the Toll-like receptor ligands poly(I:C) and flagellin. Surprisingly, the IL-36γ protein was released by cells treated with poly(I:C) but remained intracellular in cells treated with flagellin only. Poly(I:C), but not flagellin, induced cell death and caspase-3/7 activation. Inhibition of caspase-3/7 and caspase-1 blocked extracellular release of IL-36γ from poly(I:C) treated cells. Furthermore, caspase-1 inhibition prevented poly(I:C)-induced caspase-3/7 activation. Interestingly, transcription of the gene IL36G was dependent upon caspase-1, but not caspase-3/7, activation. This demonstrates that the pathways leading to IL36G transcription and caspase-3/7 activation branch after caspase-1. This divergence of the pathways allows the cells to enter a state of de novo protein synthesis before committing to pyroptosis. Overall our observations suggest that IL-36γ may be an alarmin that signals the cause, e.g. viral infection, of cell death.

IgE-mediated allergy. However, the frequency of allergen-specific CD4 + Th2-cells that produce high levels of IL-4, IL-5, and IL-13 but low levels of IFN-γ in the peripheral blood of allergic individuals is This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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