| Summary: | 碩士 === 臺北醫學大學 === 醫學科學研究所 === 97 === Abstract
Thrombin, excluding the functions in thrombosis and hemostasis, also plays an important role in the lung inflammation. Our previously report showed that c-Src mediates thrombin-induced NF-κB activation and IL-8/CXCL8 expression in lung epithelial cells. This study investigated the mechanism of the c-Src-dependent Shc/Raf-1/ERK signal pathway involved in thrombin-induced IL-8/CXCL8 release in human lung epithelial cells. Thrombin-induced IL-8/CXCL8 expression and κB-luciferase activity were inhibited by Shc siRNA. Treatment of A549 cells with thrombin caused Shc phosphorylation at Tyr-239/240 and Tyr-317 in a time-dependent manner. Transfected c-Src DN inhibited thrombin-induced Shc phosphorylation at Tyr-239/240, but not at Tyr-317. Thrombin also induced Raf-1 and ERK phosphorylation in a time-dependent manner. Pretreatment of A549 cells with GW 5074 (a Raf-1 inhibitor) and PD 98059 (a MEK inhibitor) both inhibited thrombin-induced IKKα/β phosphorylation, κB-luciferase activity, and IL-8/CXCL8 release. Furthermore, studies revealed that thrombin enhances the recruitment of PAR1, Gβ, Shc to c-Src in a time-dependent manner. Take together, these results indicated that thrombin activates the the PAR1/Gβ/c-Src-dependent Shc/Raf-1/ERK signaling pathway to induce IKKα/β/NF-κB activation, which in turn induces IL-8/CXCL8 expression and release in human lung epithelial cells.
|
|---|
