Bcl-3 induced by IL-22 via STAT3 activation acts as a potentiator of psoriasis-related gene expression in epidermal keratinocytes
Bcl-3 induced by IL-22 via STAT3 activation acts as a potentiator of psoriasis-related gene expression in epidermal keratinocytes
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DOI：
10.1002/eji.201747017
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发表时间：
2018-01-01
影响因子：
5.4
通讯作者：
Sayama, Koji
中科院分区：
文献类型：
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作者：
Tohyama, Mikiko;Shirakata, Yuji;Sayama, Koji
IL-22诱导STAT3磷酸化，介导银屑病相关基因表达。然而，从pSTAT3到这些基因表达的信号传导机制尚不清楚。我们重点研究了由STAT3激活诱导并介导基因表达的Bcl-3。在培养的人表皮角质形成细胞中，IL-22增加Bcl-3， Bcl-3通过STAT3激活p50易位到细胞核。IL-22引起的CXCL8、S100As和人β -防御素2 mRNA表达升高可通过siRNA作用于Bcl-3而被消除。虽然IL-22也增加了CCL20的表达，但Bcl-3的下调增加了其表达水平。此外，IL-22和IL-17A的结合增强了Bcl-3的产生、IL-22诱导的基因表达以及其他银屑病相关基因的表达，包括编码IL-17C、IL-19和IL-36 γ的基因。这些基因（CCL20除外）的表达也被Bcl-3的下调所抑制。Bcl-3过表达可诱导CXCL8和HBD2表达，但不能诱导S100As表达。我们还比较了银屑病皮损与正常皮肤中Bcl-3的表达。免疫染色显示银屑病皮肤表皮角质形成细胞核中Bcl-3和p50的强烈信号。IL-22-STAT3-Bcl-3通路可能在银屑病的发病机制中起重要作用。
IL-22 induces STAT3 phosphorylation and mediates psoriasis-related gene expression. However, the signaling mechanism leading from pSTAT3 to the expression of these genes remains unclear. We focused on Bcl-3, which is induced by STAT3 activation and mediates gene expression. In cultured human epidermal keratinocytes, IL-22 increased Bcl-3, which was translocated to the nucleus with p50 via STAT3 activation. The increases in CXCL8, S100As and human beta-defensin 2 mRNA expression caused by IL-22 were abolished by siRNA against Bcl-3. Although CCL20 expression was also augmented by IL-22, the knockdown of Bcl-3 increased its level. Moreover, the combination of IL-22 and IL-17A enhanced Bcl-3 production, IL-22-induced gene expression, and the expression of other psoriasis-related genes, including those encoding IL-17C, IL-19, and IL-36 gamma. The expression of these genes (except for CCL20) was also suppressed by the knockdown of Bcl-3. Bcl-3 overexpression induced CXCL8 and HBD2 expression but not S100As expression. We also compared Bcl-3 expression between psoriatic skin lesions and normal skin. Immunostaining revealed strong signals for Bcl-3 and p50 in the nucleus of epidermal keratinocytes from psoriatic skin. The IL-22-STAT3-Bcl-3 pathway may be important in the pathogenesis of psoriasis.