Corticosteroids are the preeminent antin-flammatory agents altoh the molular menims that impart their efficacy have not been defined. The endo u plays a critical role in infmmation by ding crcaing leukocytes into extravascular tissue by expr g adhesive molecules for leukocytes [e.g., endothelalleukocyte adhesion molecule 1 (ELAM-1) and intercellular ad ocule 1 (ICAM-1)]. We therefore determined whether corticosterolds suppress inflammation by inhibiting elll exp n of adhesion molecules for neutrophils (polymorphonulear leuko-cytes). Preincubation of endothelial cells with endoin [lipo-polysaccharlde (LPS), 1 pg/ml] led to a 4-fold inC in subsequent adherence of polymorphonucer leukocytes (P < 0.0001, n = 10) to endothellal cells, an ire that was markedy attenuated when endothelial cells were treated with dexamethasone (ICso < 1 nM, P < 0.0001, n = 6 or 7) during preincubation with LPS. Moreover, the steroid receptor agonist cortsol (10 pM), but not Its inactive metabolite tetrahydrocorti-sol (10 JpM), diminhed LPS-induced endothelial cell adhesive-ness. Further evidence that the action of dexamethasone was mediated through ligation of corticosteroid eceptrs [human glucocorticoid receptors (hGRs)] was provided by exits utlizing the steroid antagonist RU-486. RU-486 (10 pM), which prevents transiocation of ligted hGR to the nu ses by nhib-iting diction of hGR from heat shock protein 90, m y aborted the effect of dexamethasone on adhesiveness of endo-thelial cells (P < 0.0005, n = 3). Treatment of e e cells with LPS (1 pg/ml) stimulated t io of ELAM-1, as shown by Northern blot analysis, and expressin of membrane-associated ELAM-1 and ICAM-1, as shown by quantitative immunofluorescence (both P < 0.001, n = 9). De s_ markedly inhibited LPS-stimulated accumul of mRNA for ELAM-1 and expression of ELAM-1 and ICAM-1 (IC_% < 10 nM, both P < 0.001, n = 4-9); inhibition of exp by dexamethasone was reversed by RU-486 (both P < 0.005, n = 4-6). As in the adhesion studies, cortsol but not tetahydro cortisol inhibited expression of ELAM-1 and ICAM-1 (bothP < 0.005, n = 3 or 4). In contrast, sodium sallcylate (1 mM) inhibited neither adhesion nor expressin of these adesn molecules. These studies suggest that antan by de h-asone ofendotoxin-induced inflammation is a specifc s of the general biological principle that the glucocortcod receptor is a hormone-dependent regulator of transcription.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.