SOCS1-negative feedback of STAT1 activation is a key pathway in the dsRNA-induced innate immune response of human keratinocytes
SOCS1-negative feedback of STAT1 activation is a key pathway in the dsRNA-induced innate immune response of human keratinocytes
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DOI：
10.1038/sj.jid.5700294
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发表时间：
2006-07-01
影响因子：
6.5
通讯作者：
Hashimoto, Koji
中科院分区：
文献类型：
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作者：
Dai, Xiuju;Sayama, Koji;Hashimoto, Koji
Toll 样受体 (TLR)3 是病毒相关双链 RNA 的受体，在病毒感染期间触发抗病毒免疫反应。表皮角质形成细胞表达 TLR3，并提供针对病毒感染的先天免疫防御。由于细胞内调节机制尚不清楚，我们假设信号转导子和转录激活子（STAT）-细胞因子信号传导抑制子（SOCS）系统调节角质形成细胞的先天免疫反应。用聚肌苷-聚胞苷酸 (poly(I:C)) 处理导致 IFN 调节因子 (IRF)-3 快速易位至细胞核，随后 STAT1 和 STAT3 磷酸化。 Poly(I:C) 可能通过 Poly(I:C) 诱导的 IFN 以间接方式激活 STAT。我们使用腺病毒载体用 STAT1 (STAT1F)、STAT3 (STAT3F) 和 SOCS1 的显性失活形式感染细胞。 STAT1F 感染抑制了 Poly(I:C) 对巨噬细胞炎症蛋白 (MIP)-1 α 的诱导，而 STAT3F 的作用最小，这表明 STAT1 介导 MIP-1 α 诱导。 SOCS1 是 STAT1 信号传导的负反馈调节因子，由聚 (I:C) 处理诱导。 SOCS1 感染抑制 STAT1 的磷酸化，并显着减少 Poly(I:C) 诱导的 MIP-1 α 产生。此外，STAT1-SOCS1 调节聚 (I:C) 诱导的 TLR3 和 IRF-7 表达。然而，SOCS1 并不影响 NF-kappa B 信号传导。因此，STAT1-SOCS1 通路通过表皮角质形成细胞中的 TLR3 信号传导调节先天免疫反应。
Toll-like receptor (TLR)3 is a receptor for virus-associated double-stranded RNA, and triggers antiviral immune responses during viral infection. Epidermal keratinocytes express TLR3 and provide an innate immune defense against viral infection. Since the intracellular regulatory mechanism is unknown, we hypothesized that the signal transducers and activators of transcription (STAT)-suppressors of cytokine signaling (SOCS) system regulates the innate immune response of keratinocytes. Treatment with polyinosinic-polycytidylic acid (poly(I:C)) resulted in the rapid translocation of IFN regulatory factor (IRF)-3 into the nucleus, followed by phosphorylation of STAT1 and STAT3. The activation of STATs by poly(I:C) probably occurs in an indirect fashion, through poly(I:C)-induced IFN. We infected cells with the dominant-negative forms of STAT1 (STAT1F), STAT3 (STAT3F), and SOCS1 using adenovirus vectors. Infection with STAT1F suppressed the induction of macrophage inflammatory protein (MIP)-1 alpha by poly(I:C), whereas STAT3F had a minimal effect, which indicates that STAT1 mediates MIP-1 alpha induction. SOCS1, which is a negative feedback regulator of STAT1 signaling, was induced by treatment with poly(I:C). SOCS1 infection inhibited the phosphorylation of STAT1 and significantly reduced poly(I:C)-induced MIP-1 alpha production. Furthermore, STAT1-SOCS1 regulated poly(I:C)-induced TLR3 and IRF-7 expression. However, SOCS1 did not affect NF-kappa B signaling. Thus, the STAT1-SOCS1 pathway regulates the innate immune response via TLR3 signaling in epidermal keratinocytes.