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  • Title: Transactivation of Src, PDGF receptor, and Akt is involved in IL-1beta-induced ICAM-1 expression in A549 cells.
    Author: Lin CC, Lee CW, Chu TH, Cheng CY, Luo SF, Hsiao LD, Yang CM.
    Journal: J Cell Physiol; 2007 Jun; 211(3):771-80. PubMed ID: 17299794.
    Abstract:
    In previous study, interleukin-1beta (IL-1beta) has been shown to induce ICAM-1 expression through MAPKs and NF-kappaB in A549 cells. In addition to these pathways, transactivation of non-receptor tyrosine kinase (Src), PDGF receptors (PDGFRs), and phosphatidylinositol 3-kinase (PI3K)/Akt has been implicated in the expression of inflammatory genes. Here, we further investigated whether these different mechanisms participating in IL-1beta-induced ICAM-1 expression in A549 cells. We initially observed that IL-1beta-induced ICAM-1 promoter activity was attenuated by the inhibitors of Src (PP1), PDGFR (AG1296), PI3-K (LY294002 and wortmannin), and Akt (SH-5), revealed by reporter gene assay, Western blotting, and RT-PCR analyses. The involvement of Src and PI3-K/Akt in IL-1beta-induced ICAM-1 expression was significantly attenuated by transfection of A549 cells with dominant negative plasmids of Src, p85 and Akt, respectively. Src, PDGFR, and PI3K/Akt mediated the effects of IL-1beta because pretreatment with PP1, AG1296, and wortmannin also abrogated IL-1beta-stimulated Src, PDGFR, and Akt phosphorylation, respectively. Moreover, pretreatment with p300 inhibitor (curcumin) also blocked ICAM-1 expression. We further confirmed that p300 was associated with ICAM-1 promoter which was dynamically linked to histone H4 acetylation stimulated by IL-1beta, determined by chromatin immunoprecipitation assay. Association of p300 and histone-H4 to ICAM-1 promoter was inhibited by LY294002. Up-regulation of ICAM-1 enhanced the adhesion of neutrophils onto A549 cell monolayer exposed to IL-1beta, which was inhibited by PP1, AG1296, LY294002, wortmannin, and helenalin. These results suggested that Akt phosphorylation mediated through transactivation of Src/PDGFR promotes the transcriptional p300 activity and eventually leads to ICAM-1 expression induced by IL-1beta.
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