Interleukin-10-induced gene expression and suppressive function are selectively modulated by the PI3K-Akt-GSK3 pathway
Interleukin-10-induced gene expression and suppressive function are selectively modulated by the PI3K-Akt-GSK3 pathway
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DOI：
10.1111/j.1365-2567.2010.03402.x
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发表时间：
2011-04-01
期刊：
影响因子：
6.4
通讯作者：
Ivashkiv, Lionel B.
中科院分区：
文献类型：
--
作者：
Antoniv, Taras T.;Ivashkiv, Lionel B.
白细胞介素-10 （IL-10）是一种抑制炎症基因表达的免疫抑制细胞因子。磷脂酰肌醇3-激酶（PI3K）介导的信号传导调节炎症反应并诱导IL-10的产生，但PI3K信号传导在细胞对IL-10的反应中的作用尚不清楚。在本研究中，我们研究了PI3K-Akt-GSK3信号通路在原代人巨噬细胞中il -10诱导的基因表达和il -10介导的toll样受体诱导的基因表达抑制中的作用。在原代人巨噬细胞中，使用激酶抑制剂、组成活性Akt的表达和RNA干扰的功能丧失和获得方法的组合表明，il -10诱导基因亚群的表达依赖于PI3K-Akt信号传导。PI3K-Akt信号传导对IL-10反应的影响至少部分是由糖原合成酶激酶3 （GSK3）介导的。根据PI3K通路在抑制IL-10中的功能作用，PI3K信号通路增强了IL-10介导的对脂多糖诱导的IL-1、IL-8和环氧化酶-2表达的抑制。PI3K信号选择性地调节IL-10反应，因为它不需要抑制肿瘤坏死因子表达或诱导某些IL-10诱导基因（如SOCS3）。这些发现确定了pi3k介导的信号通过调节il -10介导的基因诱导和抗炎功能来抑制炎症的新机制。
P>Interleukin-10 (IL-10) is an immunosuppressive cytokine that inhibits inflammatory gene expression. Phosphatidylinositol 3-kinase (PI3K) -mediated signalling regulates inflammatory responses and can induce IL-10 production, but a role for PI3K signalling in cellular responses to IL-10 is not known. In this study we investigated the involvement of the PI3K-Akt-GSK3 signalling pathway in IL-10-induced gene expression and IL-10-mediated suppression of Toll-like receptor-induced gene expression in primary human macrophages. A combination of loss and gain of function approaches using kinase inhibitors, expression of constitutively active Akt, and RNA interference in primary human macrophages showed that expression of a subset of IL-10-inducible genes was dependent on PI3K-Akt signalling. The effects of PI3K-Akt signalling on IL-10 responses were mediated at least in part by glycogen synthase kinase 3 (GSK3). In accordance with a functional role for PI3K pathways in contributing to the suppressive actions of IL-10, PI3K signalling augmented IL-10-mediated inhibition of lipopolysaccharide-induced IL-1, IL-8 and cyclo-oxygenase-2 expression. The PI3K signalling selectively modulated IL-10 responses, as it was not required for inhibition of tumour necrosis factor expression or for induction of certain IL-10-inducible genes such as SOCS3. These findings identify a new mechanism by which PI3K-mediated signalling can suppress inflammation by regulating IL-10-mediated gene induction and anti-inflammatory function.