Tumor necrosis factor-α augments matrix metalloproteinase-9 production in skeletal muscle cells through the activation of transforming growth factor-β-activated kinase 1(TAK1)-dependent signaling pathway
Tumor necrosis factor-α augments matrix metalloproteinase-9 production in skeletal muscle cells through the activation of transforming growth factor-β-activated kinase 1(TAK1)-dependent signaling pathway
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DOI：
10.1074/jbc.m705329200
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发表时间：
2007-11-30
影响因子：
4.8
通讯作者：
Kumar, Ashok
中科院分区：
文献类型：
--
作者：
Srivastava, Apurva K.;Qin, Xuezhong;Kumar, Ashok
我们研究了肿瘤坏死因子-α（TNF-α）对骨骼肌细胞外基质降解蛋白酶产生的影响。使用微阵列，定量PCR，蛋白质印迹和酶谱，我们发现，TNF-α显着增加C2 C12肌管的基质金属蛋白酶（MMP）-9的生产。在小鼠体内施用TNF-α增加了骨骼肌组织中MMP-9的转录水平。尽管TNF-α激活了所有三种MAPK（即ERK 1/2、JNK和p38），但抑制ERK 1/2或p38而非JNK可减弱TNF-α诱导的肌管MMP-9的产生。抑制Akt也抑制了TNF-α诱导的MMP-9的产生。TNF-α增加了肌管中转录因子NF-κ B和AP-1的激活，但不增加SP-1的激活。显性负性NF-κ B或AP-1抑制剂的过表达阻断了肌管中TNF-α诱导的MMP-9表达。类似地，MMP-9启动子中AP-1或NF-κ B结合位点的点突变抑制TNF-α诱导的报告基因表达。TNF-α增加转化生长因子-β激活激酶-1（TAK 1）的活性。此外，TAK 1显性失活突变体的过表达阻断了TNF-α诱导的MMP-9表达以及NF-κ B和AP-1的激活。我们的研究结果还表明，TNF-α诱导MMP-9在肌细胞中的表达，通过招募TRAF-2，Fas相关蛋白与死亡结构域，TNF受体相关蛋白与死亡结构域，但不是NIK或TRAF-6蛋白。我们的结论是，TAK 1介导的途径参与了TNF-α诱导的MMP-9在骨骼肌细胞的生产。
We have investigated the effect of tumor necrosis factor-alpha (TNF-alpha) on the production of extracellular matrix-degrading proteases in skeletal muscles. Using microarray, quantitative PCR, Western blotting, and zymography, we found that TNF-alpha drastically increases the production of matrix metalloproteinase (MMP)-9 from C2C12 myotubes. In vivo administration of TNF-alpha in mice increased the transcript level of MMP-9 in skeletal muscle tissues. Although TNF-alpha activated all the three MAPKs (i.e. ERK1/2, JNK, and p38), inhibition of ERK1/2 or p38 but not JNK blunted the TNF-alpha-induced production of MMP-9 from myotubes. Inhibition of Akt also inhibited the TNF-alpha-induced production of MMP-9. TNF-alpha increased the activation of transcription factors NF-kappa B and AP-1 but not SP-1 in myotubes. Overexpression of a dominant negative inhibitor of NF-kappa B or AP-1 blocked the TNF-alpha-induced expression of MMP-9 in myotubes. Similarly, point mutations in AP-1- or NF-kappa B-binding sites in MMP-9 promoter inhibited the TNF-alpha-induced expression of a reporter gene. TNF-alpha increased the activity of transforming growth factor-beta-activating kinase-1 (TAK1). Furthermore, overexpression of a dominant negative mutant of TAK1 blocked the TNF-alpha-induced expression of MMP-9 and activation of NF-kappa B and AP-1. Our results also suggest that TNF-alpha induces MMP-9 expression in muscle cells through the recruitment of TRAF-2, Fas-associated protein with death domain, and TNF receptor-associated protein with death domain but not NIK or TRAF-6 proteins. We conclude that TAK1-mediated pathways are involved in TNF-alpha-induced MMP-9 production in skeletal muscle cells.