Dexamethasone inhibits cytokine-induced intercellular adhesion molecule-1 up-regulation on endothelial cell lines.
Intercellular adhesion molecule-1 (ICAM-1) expression on three endothelial cell lines was differently modulated by pro-inflammatory cytokines, such as interleukin-1beta and tumour necrosis factor-alpha (TNF-alpha) and the glucocorticoid hormone dexamethasone. Incubation of EA.hy926 cells with 1 microM dexamethasone prior to addition of TNF-alpha consistently reduced ICAM-1 induction by approximately 40%. EA.hy926 cell responsiveness to the steroid was validated by detecting specific dexamethasone binding, with a calculated affinity constant of 1.3 nM and a maximal number of sites of 35 x 10(3) per cell. To establish the generality of dexamethasone inhibition upon ICAM-1 up-regulation, two other endothelial cell lines were assessed. Incubation of LT4 and ECV304 cells with interleukin-1beta or TNF-alpha produced a significant increase in ICAM-1 expression on their cell surface (ranging from a 2-fold increase for interleukin-1beta to a 5-fold increase for TNF-alpha). Addition of dexamethasone was again able to significantly reduced this induction. Finally, the effect of the steroid on cytokine-induced ICAM-1 up-regulation was functionally related to its ability to suppress in vitro neutrophil trans-endothelial passage. Overall these data indicate that ICAM-1 is a likely molecular target for the anti-inflammatory action exerted by dexamethasone. Inhibition of ICAM-1 up-regulation may, at least in part, mediate the potent anti-migratory action displayed by this class of anti-inflammatory drugs.
Wheller
S K
SK
Department of Biochemical Pharmacology, The William Harvey Research Institute, London, UK.
Perretti
M
M
D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D009504:Neutrophils; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D003907:Dexamethasone