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首页> 外文期刊>Cellular Signalling >Thrombin-induced NF-κB activation and IL-8/CXCL8 release is mediated by c-Src-dependent Shc, Raf-1, and ERK pathways in lung epithelial cells
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Thrombin-induced NF-κB activation and IL-8/CXCL8 release is mediated by c-Src-dependent Shc, Raf-1, and ERK pathways in lung epithelial cells

机译：凝血酶诱导的NF-κB激活和IL-8 / CXCL8释放是由肺上皮细胞中依赖于c-Src的Shc，Raf-1和ERK途径介导的

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摘要

In addition to its functions in thrombosis and hemostasis, thrombin also plays an important role in lung inflammation. Our previous report showed that thrombin activates the protein kinase C (PKC)α/c-Src and Gβγ/Rac1/PI3K/Akt signaling pathways to induce IκB kinase α/β (IKKα/β) activation, NF-κB transactivation, and IL-8/CXCL8 expressions in human lung epithelial cells (ECs). In this study, we further investigated the mechanism of c-Src-dependent Shc, Raf-1, and extracellular signal-regulated kinase (ERK) signaling pathways involved in thrombin-induced NF-κB activation and IL-8/CXCL8 release. Thrombin-induced increases in IL-8/CXCL8 release and κB-luciferase activity were inhibited by the Shc small interfering RNA (siRNA), p66Shc siRNA, GW 5074 (a Raf-1 inhibitor), and PD98059 (a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor). Treatment of A549 cells with thrombin increased p66Shc and p46/p52Shc phosphorylation at Tyr239/240 and Tyr317, which was inhibited by cell transfection with the dominant negative mutant of c-Src (c-Src DN). Thrombin caused time-dependent phosphorylation of Raf-1 and ERK, which was attenuated by the c-Src DN. Thrombin-induced IKKα/β phosphorylation was inhibited by GW 5074 and PD98059. Treatment of cells with thrombin induced Gβγ, c-Src, and p66Shc complex formation in a time-dependent manner. Taken together, these results show for the first time that thrombin activates Shc, Raf-1, and ERK through Gβγ, c-Src, and Shc complex formation to induce IKKα/β phosphorylation, NF-κB activation, and IL-8/CXCL8 release in human lung ECs.
机译：凝血酶除具有血栓形成和止血功能外，在肺部炎症中也起着重要作用。我们以前的报告表明，凝血酶激活蛋白激酶C（PKC）α/ c-Src和Gβγ/ Rac1 / PI3K / Akt信号传导途径，从而诱导IκB激酶α/β（IKKα/β）激活，NF-κB反式激活和IL -8 / CXCL8在人肺上皮细胞（EC）中的表达。在这项研究中，我们进一步研究了参与凝血酶诱导的NF-κB活化和IL-8 / CXCL8释放的c-Src依赖性Shc，Raf-1和细胞外信号调节激酶（ERK）信号通路的机制。凝血酶诱导的IL-8 / CXCL8释放增加和κB荧光素酶活性受到Shc小干扰RNA（siRNA），p66Shc siRNA，GW 5074（Raf-1抑制剂）和PD98059（促分裂原激活的蛋白激酶）的抑制（MAPK）激酶（MEK）抑制剂）。用凝血酶处理A549细胞可增加Tyr239 / 240和Tyr317的p66Shc和p46 / p52Shc磷酸化，这可通过用c-Src显性负突变体（c-Src DN）转染来抑制。凝血酶引起Raf-1和ERK的时间依赖性磷酸化，并被c-Src DN减弱。凝血酶诱导的IKKα/β磷酸化被GW 5074和PD98059抑制。用凝血酶处理细胞以时间依赖性方式诱导Gβγ，c-Src和p66Shc复合物形成。综上所述，这些结果首次显示凝血酶通过Gβγ，c-Src和Shc复合物的形成激活Shc，Raf-1和ERK，从而诱导IKKα/β磷酸化，NF-κB激活和IL-8 / CXCL8在人肺ECs中释放。

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