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The Journal of Immunology, 2005, 174: 5823-5829.
Copyright © 2005 by The American Association of Immunologists

Inhibition of Mammalian Target of Rapamycin Potentiates Thrombin-Induced Intercellular Adhesion Molecule-1 Expression by Accelerating and Stabilizing NF-{kappa}B Activation in Endothelial Cells 1

Mohd Minhajuddin, Fabeha Fazal, Kaiser M. Bijli, Md. Ruhul Amin2 and Arshad Rahman3

Department of Pediatrics, University of Rochester School of Medicine, Rochester, New York 14642

We addressed the regulatory function of mammalian target of rapamycin (mTOR) in the mechanism of thrombin-induced ICAM-1 gene expression in endothelial cells. Pretreatment of HUVECs with rapamycin, an inhibitor of mTOR, augmented thrombin-induced ICAM-1 expression. Inhibition of mTOR by this approach promoted whereas over-expression of mTOR inhibited thrombin-induced transcriptional activity of NF-{kappa}B, an essential regulator of ICAM-1 transcription. Analysis of the NF-{kappa}B signaling pathway revealed that inhibition of mTOR potentiated I{kappa}B kinase activation resulting in a rapid and persistent phosphorylation of I{kappa}B{alpha} on Ser32 and Ser36, a requirement for I{kappa}B{alpha} degradation. Consistent with these data, we observed a more efficient and stable nuclear localization of RelA/p65 and, subsequently, the DNA binding activity of NF-{kappa}B by thrombin following mTOR inhibition. These data define a novel role of mTOR in down-regulating thrombin-induced ICAM-1 expression in endothelial cells by controlling a delayed and transient activation of NF-{kappa}B.




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