Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology
Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology
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DOI：
10.1093/emboj/20.14.3760
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发表时间：
2001-07-16
期刊：
影响因子：
11.4
通讯作者：
Kollias, G
中科院分区：
文献类型：
--
作者：
Kontoyiannis, D;Kotlyarov, A;Kollias, G
白介素10(IL-10)是炎症反应的关键抑制信号，调节肿瘤坏死因子(TNF)等潜在致病细胞因子的产生。我们的研究表明，IL-10缺陷小鼠的慢性肠炎的发展需要肿瘤坏死因子的功能，这表明IL-10/肿瘤坏死因子轴调节粘膜免疫。我们进一步表明，IL-10靶向肿瘤坏死因子mRNA的3‘AU富含元件(ARE)来抑制其翻译。而且，IL-10不改变肿瘤坏死因子mRNA的稳定性，其作用也不需要稳定性调节因子的存在，说明稳定性和翻译决定因素对肿瘤坏死因子的差异组装。IL-10对肿瘤坏死因子翻译的抑制作用主要是通过抑制激活p38/MAPK激活的蛋白激酶-2途径来实现的。这些结果表明，IL-10受体和针对肿瘤坏死因子信使核糖核酸翻译的应激激活蛋白激酶模块之间存在显著的生理上的串扰。这种串扰对于最佳的肿瘤坏死因子的产生和维持肠道内的免疫平衡是必要的。
Interleukin-10 (IL-10) is a key inhibitory signal of inflammatory responses that regulates the production of potentially pathogenic cytokines like tumor necrosis factor (TNF). We show here that the development of chronic intestinal inflammation in IL-10-deficient mice requires the function of TNF, indicating that the IL-10/TNF axis regulates mucosal immunity. We further show that IL-10 targets the 3 ' AU-rich elements (ARE) of TNF mRNA to inhibit its translation. Moreover, IL-10 does not alter TNF mRNA stability, and its action does not require the presence of the stability-regulating ARE binding factor tristetraprolin, indicating a differential assembly of stability and translation determinants on the TNF ARE. Inhibition of TNF translation by IL-10 is exerted mainly by inhibition of the activating p38/MAPK-activated protein kinase-2 pathway. These results demonstrate a physiologically significant cross-talk between the IL-10 receptor and the stress-activated protein kinase modules targeting TNF mRNA translation. This crosstalk is necessary for optimal TNF production and for the maintenance of immune homeostasis in the gut.