Heat shock protein 27 functions in inflammatory gene expression and transforming growth factor-β-activated kinase-1 (TAK1)-mediated signaling
Heat shock protein 27 functions in inflammatory gene expression and transforming growth factor-β-activated kinase-1 (TAK1)-mediated signaling
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DOI：
10.1074/jbc.m610987200
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发表时间：
2007-03-02
影响因子：
4.8
通讯作者：
Dean, Jonathan L. E.
中科院分区：
文献类型：
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作者：
Alford, Kate A.;Glennie, Sarah;Dean, Jonathan L. E.
热休克蛋白 (HSP) 27 长期以来一直被认为是 p38 丝裂原激活蛋白激酶 (MAPK) 信号通路的组成部分。 p38 MAPK 在炎症反应中具有重要功能，但 HSP27 在炎症中的作用仍不清楚。我们使用小干扰RNA抑制HeLa细胞和成纤维细胞中的HSP27表达，发现它是促炎细胞信号传导和促炎基因表达所必需的。 TAK1 的白细胞介素 (IL)-1 激活以及 p38 MAPK、JNK 及其激活剂（MKK-3、-4、-6、-7）和 IKK beta 的下游信号传导需要 HSP27。 IL-1 诱导的 ERK 激活似乎不依赖于 HSP27。 HSP27 是 IL-1 和 TNF 诱导的信号传导途径所必需的，其中最上游的常见信号传导蛋白是 TAK1。 HSP27 也是 IL-1 诱导的促炎介质、环氧合酶-2、IL-6 和 IL-8 表达所必需的。 FISP27 通过增强 p38 MAPK、MK2 下游激酶的激活来驱动 cyclooxygenase-2 和 IL-6 表达，从而稳定 cyclooxygenase-2 和 IL-6 mRNA。该机制可能不会发生在骨髓系细胞中，因为在人单核细胞和鼠巨噬细胞中检测不到 HSP27 蛋白。
Heat shock protein (HSP) 27 has long been known to be a component of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. p38 MAPK has important functions in the inflammatory response, but the role of HSP27 in inflammation has remained unknown. We have used small interfering RNAs to suppress HSP27 expression in HeLa cells and fibroblasts and found that it is required for pro-inflammatory cell signaling and the expression of pro-inflammatory genes. HSP27 is needed for the activation by interleukin (IL)-1 of TAK1 and downstream signaling by p38 MAPK, JNK, and their activators (MKK-3, -4, -6, -7) and IKK beta. IL-1-induced ERK activation appears to be independent of HSP27. HSP27 is required for both IL-1 and TNF-induced signaling pathways for which the most upstream common signaling protein is TAK1. HSP27 is also required for IL-1-induced expression of the pro-inflammatory mediators, cyclooxygenase-2, IL-6, and IL-8. FISP27 functions to drive cyclooxygenase-2 and IL-6 expression by augmenting the activation of the kinase downstream of p38 MAPK, MK2, resulting in stabilization of cyclooxygenase-2 and IL-6 mRNAs. The mechanism may not occur in cells of myeloid lineage because HSP27 protein was undetectable in human monocytes and murine macrophages.