TNFα is one of major cytokine related to pathogenesis of psoriasis and other inflammatory diseases. Inhibition of TNFα is highly effective in treatment of psoriasis and other inflammatory conditions, such as rheumatoid arthritis. Serum IL-33 levels are reported to be elevated in psoriasis patients, which correlated with disease severity. Major source of IL-33 is believed to be epithelial and endothelial cells, including epidermal keratinocytes. IL-33 activates immune cells, such as group 2 innate lymphoid cells, and induces the production of type-2 associated cytokines. We previously reported that STAT1 and STAT3 were involved in the induction of IL-33 in normal human epidermal keratinocyte (NHEKs). On the other hand, TNFα induced IL-33 temporally only at early time point via the NFκB signal and its expression was suppressed at 24hr after stimulation. However, some groups reported that TNFα induced IL-33 in various cell types including NHEKs, which has been controversial. In this study, we analyzed mechanisms of regulation of IL-33 expression by TNFα in NHEKs. TNFα did not affect phosphorylation of STAT1 or STAT3 induced by IFNγ and/or OSM. Several miRNAs, such as miR-141, miR-487b and miR-494b, suppressed IL-33 expression and one which provides RNA stability was reported to involve IL-33 mRNA, however these factors were not induced by TNFα. Fli1 is a transcriptional factor recently revealed to suppress IL-33 expression in human fibroblast. We found that TNFα induced Fli1 expression both at mRNA and protein levels, and induced Fli1 binding to promoter region of IL-33. IFNγ and/or OSM did not induce Fli1 expression or did not enhance binding to promoter region of IL-33. We speculate that TNFα suppressed IL-33 promoter activity through induction of Fli1 expression, which in turn bind to IL-33 promoter, and consequently, suppressed the IL-33 promoter activity in NHEKs.

Regulation of IL-33 gene expression by TNFα in normal human epidermal keratinocytes