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
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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DOI：
10.1016/j.cellsig.2007.08.013
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发表时间：
2007-12-01
影响因子：
4.8
通讯作者：
Zafarullah, Muhammad
中科院分区：
文献类型：
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作者：
Ahmad, Rasheed;Sylvester, Judith;Zafarullah, Muhammad
白细胞介素-1（IL-1）是主要的原型促炎细胞因子，其通过诱导显著的II型胶原降解基质金属蛋白酶-13（MMP-13）来刺激关节炎中的软骨降解。目前尚不清楚衔接蛋白MyD 88、IRAK 1和TRAF 6参与MMP-13的调节。在这里，我们首次研究了这些蛋白在IL-1调节的软骨细胞MMP-13表达中的作用。MyD 88同源二聚化抑制肽可降低MMP-13基因表达、启动子活性、丝裂原活化蛋白激酶（MAPK）磷酸化、c-Jun和活化蛋白1（AP-1）活性。通过RNA干扰（RNAi）敲低MyD 88、IRAK 1和TRAF 6显著下调IL-1诱导的MMP-13 mRNA和蛋白水平的表达以及MMP-13启动子驱动的荧光素酶活性。非特异性对照siRNA没有效果。MMP-13抑制的机制涉及ERK、p38、JNK和c-Jun的磷酸化以及AP-1转录因子结合活性的降低。这里提出的遗传证据表明，MyD 88，IRAK 1和TRAF 6蛋白是IL-1诱导的MMP-13通过MAPK途径和AP-1活性调节的关键早期介质。这些蛋白质可以构成MMP-13引起的关节炎相关软骨损失的重要治疗靶点。(C)2007年爱思唯尔公司All rights reserved.
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.