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-kappaB, an essential regulator of ICAM-1 transcription. Analysis of the NF-kappaB signaling pathway revealed that inhibition of mTOR potentiated IkappaB kinase activation resulting in a rapid and persistent phosphorylation of IkappaBalpha on Ser32 and Ser36, a requirement for IkappaBalpha 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-kappaB 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-kappaB.
Minhajuddin, M., Fazal, F., Bijli, K. M., Amin, M. R., & Rahman, A. (2014). Inhibition of Mammalian Target of Rapamycin Potentiates Thrombin-Induced Intercellular Adhesion Molecule-1 Expression by Accelerating and Stabilizing NF- B Activation in Endothelial Cells. The Journal of Immunology, 174(9), 5823–5829. https://doi.org/10.4049/jimmunol.174.9.5823