title: Transactivation of Src, PDGF receptor, and Akt is involved in IL-1beta-induced ICAM-1 expression in A549 cells.
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.
authors.affiliation: Department of Anesthetics, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Chiang-Wen
authors.initials: CW
authors.lastname: Lee
authors.forename: Tzu-Hua
authors.initials: TH
authors.lastname: Chu
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Cheng
authors.forename: Shue-Fen
authors.initials: SF
authors.lastname: Luo
authors.forename: Li-Der
authors.initials: LD
authors.lastname: Hsiao
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
mesh_terms: D000107:Acetylation; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D053583:Interleukin-1beta / Q000494:pharmacology*; D008175:Lung Neoplasms; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D006657:Histones; D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D050880:p300-CBP Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases