Department of Dermatology, Jichi Medical University, Tochigi, Japan.
J Invest Dermatol. 2012 Nov;132(11):2593-600. doi: 10.1038/jid.2012.185. Epub 2012 Jun 7.
IL-33, a member of the IL-1 family, is implicated in type 2 T helper cell immune reactions and acts as an "alarmin" to induce activation of dendritic cells in response to external stimuli. We investigated the effect of inflammatory cytokines on IL-33 expression in normal human epidermal keratinocytes. IFN-γ dose- and time-dependently induced IL-33 expression in protein and mRNA; this was dependent on extracellular signal-regulated kinase, p38, EGFR, and JAK phosphorylation. Combined IFN-γ and tumor necrosis factor (TNF)-α treatment induced expression of a 20-kDa band corresponding to mature IL-33, which was abolished by the addition of a calpain inhibitor. The addition of the inhibitor to IFN-γ and TNF-α-stimulated cells also induced strong expression of a 25-kDa band. Small interference (si) RNA for IL-33 abolished expression of the smaller bands and the 30-kDa IL-33 band, suggesting that these IL-33 forms were IL-33 transcription products. Recombinant IL-33 added in the medium induced IL-8 production, and RNA knockdown by siRNA enhanced IL-8 expression, suggesting its dual role as a cytokine and a nuclear factor. These results indicate that IL-33 has a role in inflammatory skin diseases, in which IFN-γ and TNF-α are present in high levels.
IL-33，IL-1 家族的一员，与 2 型 T 辅助细胞免疫反应有关，并作为一种“警报素”，在对外界刺激作出反应时，诱导树突状细胞的激活。我们研究了炎性细胞因子对正常人类表皮角质形成细胞中 IL-33 表达的影响。IFN-γ 呈剂量和时间依赖性地上调蛋白质和 mRNA 中的 IL-33 表达；这依赖于细胞外信号调节激酶、p38、EGFR 和 JAK 的磷酸化。IFN-γ 和肿瘤坏死因子 (TNF)-α 的联合处理诱导与成熟的 IL-33 对应的 20-kDa 带的表达，而该表达被钙蛋白酶抑制剂所消除。抑制剂的加入也会诱导 IFN-γ 和 TNF-α 刺激的细胞中强烈表达 25-kDa 带。针对 IL-33 的小干扰 (si) RNA 消除了较小的带和 30-kDa 的 IL-33 带的表达，表明这些 IL-33 形式是 IL-33 的转录产物。添加到培养基中的重组 IL-33 诱导 IL-8 的产生，而 siRNA 的 RNA 敲低增强了 IL-8 的表达，表明其作为细胞因子和核因子的双重作用。这些结果表明，IL-33 在炎症性皮肤病中具有一定作用，其中 IFN-γ 和 TNF-α 以高水平存在。
