title: ICAM-1 induction by TNFalpha and IL-6 is mediated by distinct pathways via Rac in endothelial cells.
abstract: Atherogenesis is a chronic inflammatory response and intercellular adhesion molecule (ICAM-1) induced by cytokines plays a role in this event. In this study, the molecular mechanisms of tumor neurosis factor alpha (TNFalpha)- and IL-6-induced ICAM-1 gene expression in endothelial cells (ECs) were examined. ECs infected with adenovirus carrying the dominant negative mutant of Rac (Ad-RacN17) exhibited inhibition in both TNFalpha- and IL-6-induced ICAM-1 expression. Consistently, ECs transfected with RacN17 inhibited both TNFalpha- and IL-6-induced ICAM-1 promoter activities. Functional analysis of ICAM-1 promoter, however, indicated that the cis-acting elements in response to TNFalpha and IL-6 are different. The NFkappaB binding site in the ICAM-1 promoter region was crucial for TNFalpha-induced ICAM-1 expression but not for the induction by IL-6. ECs infected with Ad-RacN17 attenuated the TNFalpha-induced NFkappaB binding activity. In contrast, IL-6 activated a transcriptional factor, signal transducer and activator of transcription-3 (Stat3) via the phosphorylation of Tyr705 at Stat3. ECs transfected with the dominant negative mutant of Stat3 (Stat3F) demonstrated that Stat3 was required for IL-6-induced ICAM-1 gene expression. Interestingly, the phosphorylation of Tyr705 and Ser727 in Stat3 was greatly inhibited in IL-6-treated ECs previously infected with Ad-RacN17. Our data strongly indicated that ICAM-1 gene induction by TNFalpha and IL-6 is mediated mainly via NFkappaB and Stat3, respectively and Rac1 appears to play a central role in modulating cytokine-induced ICAM-1 expression in ECs.
authors.affiliation: Department of Applied Microbiology, National Chiayi University, Chiayi, Taiwan.
authors.forename: B S
authors.initials: BS
authors.lastname: Wung
authors.forename: C W
authors.initials: CW
authors.lastname: Ni
authors.forename: D L
authors.initials: DL
authors.lastname: Wang
mesh_terms: D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D020830:rac1 GTP-Binding Protein