Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells
Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells
复制标题
DOI：
10.1038/leu.2008.301
复制
发表时间：
2009-03-01
期刊：
影响因子：
11.4
通讯作者：
Brossart, P.
中科院分区：
文献类型：
--
作者：
Knoedler, A.;Schmidt, S. M.;Brossart, P.
Toll样受体（TLR）的作用是感知微生物产物的环境，并将危险信号提交给抗原呈递细胞（APC），从而激活复杂的免疫反应。在这项研究中，我们分析了在白细胞介素（IL）-10的存在下，TLR配体激活体外产生的人单核细胞来源的APC的功能。这些APC暴露于IL-10导致响应于TLR配体提供的刺激的偏斜的表型成熟，减少的细胞因子产生，例如IL-12、IL-6或肿瘤坏死因子-α，以及刺激T细胞活化的能力受损。此外，暴露于TLR刺激的APC中的CCR 7上调以及向CCL 19/MIP-3b的迁移强烈减少。发现IL-10下调MyD 88、IRAK 1（IL-1受体相关激酶）和肿瘤坏死因子受体相关因子6（TLR信号传导的必需衔接分子），并降低TLR诱导的核因子-κ B转录因子c-Rel和Rel-B以及干扰素调节因子（IRF）-3和IRF-8的核表达。这不是由于丝裂原活化蛋白激酶途径的抑制，而是通过阻断PI 3 K信号级联介导的。有趣的是，TLR信号转导相关蛋白如MyD 88、IRAK 1和哺乳动物雷帕霉素靶蛋白的抑制是由于选择性转录后调节。
Toll-like receptors (TLRs) act to sense the environment for microbial products and submit danger signals to antigen-presenting cells (APCs) resulting in activation of complex immune responses. In this study, we analyzed the function of human monocyte-derived APCs generated in vitro in the presence of interleukin (IL)-10 upon activation by TLR ligands. Exposure of these APCs to IL-10 resulted in a skewed phenotypic maturation in response to stimuli provided by the TLR ligands, a reduced cytokine production, such as IL-12, IL-6 or tumor necrosis factor-alpha, and impaired capacity to stimulate T-cell activation. Furthermore, CCR7 upregulation in APCs exposed to TLR stimulation as well as migration towards CCL19/MIP-3b were strongly reduced. IL-10 was found to downregulate MyD88, IRAK1 (IL-1 receptor-associated kinase) and tumor necrosis factor receptor-associated factor 6, essential adaptor molecules for TLR signaling, and to decrease TLR-induced nuclear expression of the nuclear factor-kappa B transcription factors c-Rel and Rel-B as well as interferon regulatory factor (IRF)-3 and IRF-8. This was not due to the inhibition of the mitogen-activated protein kinase pathway, but was rather mediated by the blockage of the PI3K signaling cascade. Interestingly, the inhibition of proteins involved in TLR signaling, such as MyD88, IRAK1 and mammalian target of rapamycin, was due to a selective post-transcriptional regulation.