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首页> 外文期刊>Cellular Signalling >MyD88, IRAK1 and TRAF6 knockdown in human chondrocytes inhibits interleukin-1-induced matrix metalloproteinase-13 gene expression and promoter activity by impairing MAP kinase activation
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MyD88, IRAK1 and TRAF6 knockdown in human chondrocytes inhibits interleukin-1-induced matrix metalloproteinase-13 gene expression and promoter activity by impairing MAP kinase activation

机译:人软骨细胞中的MyD88,IRAK1和TRAF6敲低可通过削弱MAP激酶激活来抑制白介素1诱导的基质金属蛋白酶13基因表达和启动子活性

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摘要

Interleukin-1 (IL-1) is the major prototypic proinflammatory cytokine that stimulates degradation of cartilage in arthritis by inducing prominent collagen II-degrading matrix metalloproteinase-13 (MMP-13). Nothing is known about the involvement of adaptor proteins, MyD88, IRAK1 and TRAF6 in MMP-13 regulation. Here we investigated for the first time the role of these proteins in IL-1-regulated MMP-13 expression in chondrocytes. MyD88 homodimerization inhibitory peptide diminished the expression of MMP-13 gene, promoter activity, phosphorylation of mitogen-activated protein kinases (MAPKs), c-Jun and activating protein 1 (AP-1) activity. Knockdown of MyD88, IRAK1 and TRAF6 by RNA interference (RNAi) drastically down-regulated the expression of IL-1-induced MMP-13 mRNA and protein levels and MMP-13 promoter-driven luciferase activity. Non-specific control siRNA had no effect. Mechanisms of MMP-13 inhibition involved reduced phosphorylation of ERK, p38, JNK and c-Jun as well as AP-1 transcription factor binding activity. The genetic evidence presented here demonstrates that MyD88, IRAK1 and TRAF6 proteins are crucial early mediators for the IL-1-induced MMP-13 regulation through MAPK pathways and AP-1 activity. These proteins could constitute important therapeutic targets for arthritis-associated cartilage loss by MMP-13. (C) 2007 Elsevier Inc. All rights reserved.
机译:白细胞介素-1(IL-1)是主要的原型促炎细胞因子,可通过诱导突出的胶原II降解基质金属蛋白酶13(MMP-13)来刺激关节炎中的软骨降解。关于衔接子蛋白,MyD88,IRAK1和TRAF6参与MMP-13调控的情况一无所知。在这里,我们首次研究了这些蛋白质在软骨细胞中IL-1调节的MMP-13表达中的作用。 MyD88同型二聚化抑制肽可降低MMP-13基因的表达,启动子活性,丝裂原活化蛋白激酶(MAPK)的磷酸化,c-Jun和活化蛋白1(AP-1)活性。通过RNA干扰(RNAi)抑制MyD88,IRAK1和TRAF6,可大幅下调IL-1诱导的MMP-13 mRNA和蛋白的表达以及MMP-13启动子驱动的荧光素酶活性。非特异性对照siRNA没有作用。 MMP-13抑制机制涉及减少ERK,p38,JNK和c-Jun的磷酸化以及AP-1转录因子结合活性。此处提供的遗传证据表明,MyD88,IRAK1和TRAF6蛋白是通过MAPK途径和AP-1活性对IL-1诱导的MMP-13调控的关键早期介质。这些蛋白质可能构成MMP-13与关节炎相关的软骨丧失的重要治疗靶标。 (C)2007 Elsevier Inc.保留所有权利。

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