Phosphatase PTP1B negatively regulates MyD88- and TRIF-dependent proinflammatory cytokine and type I interferon production in TLR-triggered macrophages
Phosphatase PTP1B negatively regulates MyD88- and TRIF-dependent proinflammatory cytokine and type I interferon production in TLR-triggered macrophages
复制标题
DOI：
10.1016/j.molimm.2008.05.006
复制
发表时间：
2008-08-01
影响因子：
3.6
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
--
作者：
Xu, Hongmei;An, Huazhang;Cao, Xuetao
Toll样受体（Toll like receptor，TLR）是检测微生物保守模式的主要传感器，是机体天然免疫的重要组成部分。蛋白酪氨酸磷酸酶-1B（Protein tyrosine phosphatase-1B，PTP 1B）是胰岛素途径和其他细胞信号转导的重要负调控因子，但PTP 1B是否以及如何调节TLR引发的先天性应答仍有待研究。我们在此报道PTP 1B可以显著降低LPS、CpG ODN或Poly 1：C刺激的巨噬细胞产生TNF-α、IL-6和IFN-β。因此，在用TLR配体刺激的巨噬细胞中，内源性PTP 1B表达的敲低增加了TNF-α、IL-6和IFN-β的产生。磷酸酶活性被破坏的突变体PTP 1B不能抑制TLR触发的促炎细胞因子和IFN-β的产生，表明PTP 1B以磷酸酶依赖性方式发挥其抑制活性。PTP 1 B抑制TLR配体诱导的MAPK、NF-κ B和IRF 3的活化，此外，共转染PTP 1 B以剂量依赖性方式抑制MyD 88和TRIF诱导的TNF-α和IFN-β报告基因的转录。此外，PTP 1B抑制LPS诱导的Tyk 2和STAT 1活化。因此，我们证明磷酸酶PTP 1B是TLR信号传导的生理负调节剂，通过抑制巨噬细胞中MyD 88和TRIF依赖的促炎细胞因子和IFN-β的产生。我们的研究结果为TLR反应的负性调节提供了新的机制解释，并提示PTP 1B是炎症性疾病干预的潜在靶点。(C)2008爱思唯尔有限公司保留所有权利。
Toll-like receptors (TLRs) are primary sensors to detect conserved patterns on microorganisms, thus acting as the important components of innate immunity against invading pathogens. Protein tyrosine phosphatase-1B (PTP1B) has been shown to be a critical negative regulator of insulin pathway and other cellular signaling, however, whether and how PTP1B regulates TLR-triggered innate response remain to be investigated. We report here that PTP1B can markedly decrease TNF-alpha, IL-6 and IFN-beta production by macrophages stimulated with LPS, CpG ODN, or Poly 1:C. Accordingly, knockdown of enclogenous PTP1B expression increases production of TNF-alpha, IL-6 and IFN-beta in macrophages stimulated with TLR ligands. Phosphatase activity-disrupted mutant PTP1B cannot inhibit TLR-triggered production of proinflammatory cytokines and IFN-beta, indicating PTP1B exerts its suppressive activity in phosphatase-dependent manner. PTP1B inhibits TLR ligands-induced activation of MAPKs, NF-kappa B, and IRF3, furthermore, cotransfection of PTP1B inhibits both MyD88- and TRIF-induced transcription of TNF-alpha and IFN-beta reporter genes in a dose-dependent manner. In addition, PTP1B inhibits LPS-induced Tyk2 and STAT1 activation. Therefore, we demonstrate that phosphatase PTP1B is a physiological negative regulator of TLR signaling via suppression of both MyD88- and TRIF-dependent production of proinflammatory cytokine and IFN-beta in macrophages. Our results provide new mechanistic explanation for negative regulation TLR response and suggest PTP1B as a potential target for the intervention of the inflammatory diseases. (C) 2008 Elsevier Ltd. All rights reserved.