RelA/p65 inhibition prevents tendon adhesion by modulating inflammation, cell proliferation, and apoptosis.
RelA/p65 inhibition prevents tendon adhesion by modulating inflammation, cell proliferation, and apoptosis.
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RelA/p65 抑制通过调节炎症、细胞增殖和凋亡来防止肌腱粘附
DOI：
10.1038/cddis.2017.135
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发表时间：
2017-03-30
影响因子：
9
通讯作者：
Fan C
中科院分区：
文献类型：
--
作者：
Chen S;Jiang S;Zheng W;Tu B;Liu S;Ruan H;Fan C
腱鞘组织纤维化导致肌腱功能不良是一个世界性的临床问题；然而，其机制尚不清楚。转录因子RelA/p65是NF-κB复合体的一个重要亚基，在许多纤维化疾病中起关键作用。在这里，我们发现RelA/p65在肌腱粘连中起着核心纤维化调节作用，其抑制作用对腱鞘粘连具有抗纤维化作用。我们利用基因芯片芯片技术检测人肌腱粘附过程中NF-κB通路的上调，并通过免疫组化和western blotting检测p65和细胞外基质（ECM）蛋白Collagen I、Collagen III和α-平滑肌肌动蛋白（α-SMA）在人纤维化组织中的过表达。我们还发现，在肌腱损伤大鼠模型中，p65的表达与肌腱粘连相关，而通过宏观、生物力学、组织学、免疫组织化学和免疫印迹分析，小干扰（si）RNA对p65的抑制可以阻止纤维组织的形成和炎症反应。此外，在培养成纤维细胞中，p65-siRNA、p65特异性抑制剂、Helenalin和JSH23抑制细胞增殖和促进细胞凋亡，同时抑制ECM成分和环氧化酶-2（一种参与肌腱粘附的炎症因子）的mRNA和蛋白表达。我们的研究结果表明p65在肌腱周围组织纤维化中起关键作用，并表明p65敲除可能是一种有希望的预防肌腱粘连的治疗方法。
Peritendinous tissue fibrosis which leads to poor tendon function is a worldwide clinical problem; however, its mechanism remains unclear. Transcription factor RelA/p65, an important subunit in the NF-κB complex, is known to have a critical role in many fibrotic diseases. Here, we show that RelA/p65 functions as a core fibrogenic regulator in tendon adhesion and that its inhibition exerts an anti-fibrogenic effect on peritendinous adhesion. We detected the upregulation of the NF-κB pathway in human tendon adhesion using a gene chip microarray assay and revealed the overexpression of p65 and extracellular matrix (ECM) proteins Collagen I, Collagen III, and α-smooth muscle actin (α-SMA) in human fibrotic tissues by immunohistochemistry and western blotting. We also found that in a rat model of tendon injury, p65 expression correlated with tendon adhesion, whereas its inhibition by small interfering (si)RNA prevented fibrous tissue formation and inflammatory reaction as evidenced by macroscopic, biomechanical, histological, immunohistochemical, and western blotting analyses. Furthermore, in cultured fibroblasts, p65-siRNA, p65-specific inhibitor, Helenalin and JSH23 suppressed cell proliferation and promoted apoptosis, whereas inhibiting the mRNA and protein expression of ECM components and cyclo-oxygenase-2, an inflammatory factor involved in tendon adhesion. Our findings indicate that p65 has a critical role in peritendinous tissue fibrosis and suggest that p65 knockdown may be a promising therapeutic approach to prevent tendon adhesion.