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ICAM-1 induction by TNFα and IL-6 is mediated by distinct pathways via Rac in endothelial cells

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Journal of Biomedical Science

Summary

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 α (TNFα)- 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 TNFα- and IL-6-induced ICAM-1 expression. Consistently, ECs transfected with RacN17 inhibited both TNFα- and IL-6-induced ICAM-1 promoter activities. Functional analysis of ICAM-1 promoter, however, indicated that the cis-acting elements in response to TNFα and IL-6 are different. The NFκB binding site in the ICAM-1 promoter region was crucial for TNFα-induced ICAM-1 expression but not for the induction by IL-6. ECs infected with Ad-RacN17 attenuated the TNFα-induced NFκB 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 TNFα and IL-6 is mediated mainly via NFκB and Stat3, respectively and Rac1 appears to play a central role in modulating cytokine-induced ICAM-1 expression in ECs.

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Authors and Affiliations

  1. Department of Applied Microbiology, National Chiayi University, Chiayi, Taiwan

    B. S. Wung

  2. Cardiovascular Division, Academia Sinica, Institute of Biomedical Sciences, Taipei, Taiwan

    C. W. Ni & D. L. Wang

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  1. B. S. Wung
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  2. C. W. Ni
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Wung, B.S., Ni, C.W. & Wang, D.L. ICAM-1 induction by TNFα and IL-6 is mediated by distinct pathways via Rac in endothelial cells. J Biomed Sci 12, 91–101 (2005). https://doi.org/10.1007/s11373-004-8170-z

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