Thrombin induces ICAM-1 expression in human lung epithelial cells via c-Src/PDGFR/PI3K/Akt-dependent NF-{kappa}B/p300 activation

Up-regulation of intercellular adhesion molecule-1 (ICAM-1) is frequently implicated in lung inflammation and lung diseases, such as idiopathic pulmonary fibrosis (IPF). Thrombin has been shown to play a key role in inflammation via adhesion molecules induction, and then causes lung injury. However, the mechanisms underlying thrombin-induced ICAM-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain unclear. We showed that thrombin induced ICAM-1 expression in HPAEpiCs. Pretreatment with the inhibitor of thrombin (PPACK), c-Src (PP1), PDGFR (AG1296), PI3K (LY294002), NF-κB (Bay11-7082), or p300 (GR343) and transfection with siRNAs of c-Src, PDGFR, Akt, p65, and p300 markedly reduced thrombin-induced ICAM-1 expression and monocyte adherence to HPAEpiCs challenged with thrombin. In addition, we established that thrombin stimulated phosphorylation of c-Src, PDGFR, Akt, or p65, which were inhibited by pretreatment with their respective inhibitor PP1, AG1296, LY294002, or Bay11-7082. On the other hand, thrombin also enhanced Akt and NF-κB translocation from the cytosol to the nucleus, which were reduced by PP1, AG1296, or LY294002. Thrombin induced NF-κB promoter activity and the formation of p65/Akt/p300 complex, which were inhibited by AG1296, LY294002, or PP1. Finally, we showed that thrombin stimulated in vivo binding of p300, Akt, or p65 to the ICAM-1 promoter, which was reduced by AG1296, LY294002, SH-5, or PP1. These results showed...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research