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首页> 外文期刊>American Journal of Physiology >TNF-alpha induces MMP-9 expression via activation of Src/EGFR, PDGFR/PI3K/Akt cascade and promotion of NF-kappaB/p300 binding in human tracheal smooth muscle cells.
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TNF-alpha induces MMP-9 expression via activation of Src/EGFR, PDGFR/PI3K/Akt cascade and promotion of NF-kappaB/p300 binding in human tracheal smooth muscle cells.

机译：TNF-α通过激活Src / EGFR，PDGFR / PI3K / Akt级联并促进人气管平滑肌细胞中NF-κB/ p300结合来诱导MMP-9表达。

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摘要

TNF-alpha has been shown to induce matrix metalloproteinase-9 (MMP-9) expression, which, in turn, degrades extracellular matrix in the inflammatory responses. However, the inductive mechanisms of the MMP-9 by TNF-alpha remain unclear. In human tracheal smooth muscle cells, TNF-alpha induced MMP-9 expression and Akt phosphorylation in a time-dependent manner, which was attenuated by the inhibitors of Src (PP1), epidermal growth factor receptor (AG1478), PDGFR (AG1296), and PI3K (LY294002), respectively, revealed by reporter gene assay, RT-PCR, zymographic, and Western blot analyses. Transfection with the dominant negative mutants of c-Src (KM, K295M [kinase inactive mutant]), p85, and Akt (KA, K179A) also reduced MMP-9 expression. These findings indicated that MMP-9 expression was regulated by PI3K/Akt via the transactivation of growth factor receptors. Furthermore, LY294002 or wortmannin inhibited Akt phosphorylation but had no effect on NF-kappaB translocation, which was blocked by helenalin. Mutated NF-kappaB DNA binding element in the MMP-9 promoter and helenalin also attenuated MMP-9 expression, suggesting that PI3K/Akt and NF-kappaB independently regulated MMP-9 expression. To support this notion, immunofluorescence staining and immunoprecipitation were applied to characterize the transcription factors involved in these responses. The results showed that LY294002 and curcumin blocked Akt translocation into nucleus. In contrast, p300, acetyl-histone (H3), and NF-kappaB p65 were found to be coimmunoprecipitated with the phosphorylated Akt, indicating that these components associated with the MMP-9 promoter are revealed by chromatin immunoprecipitation assay. Thus, our study provides a new insight into the molecular mechanisms that TNF-alpha-stimulated Akt phosphorylation mediated through transactivation of Src and growth factor receptors may stimulate the recruitment of p300, assemble transcription factor (p65), and then lead to MMP-9 expression.
机译：TNF-α已被证明可诱导基质金属蛋白酶9（MMP-9）表达，进而在炎症反应中降解细胞外基质。但是，尚不清楚TNF-α对MMP-9的诱导机制。在人类气管平滑肌细胞中，TNF-α以时间依赖性方式诱导MMP-9表达和Akt磷酸化，并被Src（PP1），表皮生长因子受体（AG1478），PDGFR（AG1296），和PI3K（LY294002）分别通过报告基因测定，RT-PCR，酶谱和Western印迹分析揭示。用c-Src（KM，K295M [激酶非活性突变体]），p85和Akt（KA，K179A）的显性负突变体进行转染也降低了MMP-9的表达。这些发现表明，MMP-9表达通过生长因子受体的反式激活受到PI3K / Akt的调节。此外，LY294002或渥曼青霉素可抑制Akt磷酸化，但对Helalalin阻止的NF-κB易位没有影响。 MMP-9启动子和海蓝素中突变的NF-κBDNA结合元件也减弱了MMP-9的表达，提示PI3K / Akt和NF-κB独立调节MMP-9的表达。为了支持该观点，应用了免疫荧光染色和免疫沉淀来表征参与这些应答的转录因子。结果表明，LY294002和姜黄素可阻止Akt转运入细胞核。相反，发现p300，乙酰基组蛋白（H3）和NF-kappaB p65与磷酸化的Akt发生了共免疫沉淀，这表明与MMP-9启动子相关的这些成分通过染色质免疫沉淀测定法得以揭示。因此，我们的研究为通过Src和生长因子受体的反式激活介导的TNF-α刺激的Akt磷酸化可能刺激p300募集，装配转录因子（p65），然后导致MMP-9的分子机制提供了新的见解。表达。

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