Differential post-transcriptional regulation of IL-10 by TLR2 and TLR4-activated macrophages.
Differential post-transcriptional regulation of IL-10 by TLR2 and TLR4-activated macrophages.
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DOI：
10.1002/eji.201343734
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发表时间：
2014-03
影响因子：
5.4
通讯作者：
Saraiva M
中科院分区：
文献类型：
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作者：
Teixeira-Coelho M;Guedes J;Ferreirinha P;Howes A;Pedrosa J;Rodrigues F;Lai WS;Blackshear PJ;O'Garra A;Castro AG;Saraiva M
微生物分子激活TLRs，触发细胞内信号级联反应和IL-10等细胞因子的表达。IL10的表达受到严格控制，以确保有效的免疫反应，同时防止病理。TLR在巨噬细胞中最大限度地诱导IL10转录需要通过MAPKs、ERK和p38来传递信号。通过TLR4激活下游的p38信号也在转录后水平调节IL-10，但这一机制是否作用于其他TLRs下游尚不清楚。我们比较了TLR2和TLR4刺激的骨髓来源的巨噬细胞对IL-10产生的调节，发现了不同的IL10mRNA的稳定性。TLR2信号促进IL10mRNA的快速诱导和降解，而TLR4信号则通过激活Toll/IL-1受体结构域适配子诱导干扰素-β(TRIF)和增强p38信号而保护IL10mRNA不被快速降解。这种不同的转录后机制有助于通过TLR4更强地诱导IL-10的分泌。我们的研究为TLR2或TLR4刺激的骨髓基质细胞产生不同的IL-10提供了分子机制，表明p38诱导的稳定性并不是所有TLR信号通路都共有的。当细菌激活BMMS中的TLR2或TLR4时，也可以观察到这一机制，有助于在感染环境中对这些细胞中的IL-10进行调节。
The activation of TLRs by microbial molecules triggers intracellular-signaling cascades and the expression of cytokines such as IL-10. Il10 expression is tightly controlled to ensure effective immune responses, while preventing pathology. Maximal TLR-induction of Il10 transcription in macrophages requires signaling through the MAPKs, ERK, and p38. Signals via p38 downstream of TLR4 activation also regulate IL-10 at the post-transcriptional level, but whether this mechanism operates downstream of other TLRs is not clear. We compared the regulation of IL-10 production in TLR2 and TLR4-stimulated BM-derived macrophages and found different stability profiles for the Il10 mRNA. TLR2 signals promoted a rapid induction and degradation of Il10 mRNA, whereas TLR4 signals protected Il10 mRNA from rapid degradation, due to the activation of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and enhanced p38 signaling. This differential post-transcriptional mechanism contributes to a stronger induction of IL-10 secretion via TLR4. Our study provides a molecular mechanism for the differential IL-10 production by TLR2- or TLR4-stimulated BMMs, showing that p38-induced stability is not common to all TLR-signaling pathways. This mechanism is also observed upon bacterial activation of TLR2 or TLR4 in BMMs, contributing to IL-10 modulation in these cells in an infection setting.