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Expression of IL-33 in the epidermis: The mechanism of induction by IL-17

      Abstract

      Background

      Interleukin (IL)-33 is a dual functional, IL-1 family member cytokine, whose exact roles in inflammatory skin diseases are still unknown. IL-17A is a key cytokine in the pathogenesis of psoriasis.

      Objectives

      We investigated if IL-17A could induce IL-33 in epidermal keratinocytes, and the signaling mechanisms involved.

      Methods

      IL-33 levels were evaluated by RT-PCR and western blot in human keratinocytes following IL-17A simulation. IL-33 immunohistochemical staining of psoriatic skin samples was also performed and compared with that of control tissues. The role of signaling pathways downstream of IL-17A was investigated using small molecule inhibitors of EGFR, ERK, p38, and JAK. Adenovirus vector expressing dominant negative STAT1 was also utilized.

      Results

      IL-33 and its receptor, ST2L, were expressed in the psoriatic epidermis, and the associated infiltrating cells. IL-17A induced IL-33 expression at mRNA and protein levels in a time- and concentration-dependent manner. IL-17A caused phosphorylation of EGFR, ERK, p38, and STAT1. IL-17A-induced IL-33 expression was blocked by the addition of EGFR, ERK, p38, and JAK inhibitors, and dominant negative STAT1-expressing adenovirus vector.

      Conclusion

      IL-17A induced IL-33 in NHEKs through EGFR, ERK, p38, and JAK/STAT1 pathways, which were necessary for the induction of IL-33. IL-33, induced by IL-17A in epidermal keratinocytes, may be involved in the pathophysiology of inflammatory skin diseases, including psoriasis.

      Keywords

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