A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1.

Abstract

Corticosteroids are the preeminent antinflammatory agents altoh the molular menims that impart their efficacy have not been defined. shown by Northern blot analysis, and expressin of membraneassociated 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 hasone ofendotoxin-induced inflammation is a specifc s of the general biological principle that the glucocortcod receptor is a hormone-dependent regulator of transcription.

Bronchial angiogenesis in severe glucocorticoid-dependent asthma

“…The consistent decrease in numbers of vessels expressing E-selectin found in severe asthma relative to mild disease may possibly be due to the inhibitory effects of high doses of glucocorticoids [25], involving nuclear factor (NF)-kB inhibition [30]. However, functional antagonism between the glucocorticoid receptor and NF-kB has also been described in the transcriptional regulation of genes encoding for IL-8 and ICAM-1 [30], which has been shown in this and a previous study [31] to be insufficiently downregulated in severe asthma.…”

“…The authors cannot exclude the possibility that the anti-inflammatory effects of glucocorticoids may have influenced vascular expression of adhesion molecules [25± 27]. In a recent study, pretreatment of endothelial cells with glucocorticoids for 4 h prevented adhesion of neutrophils and diminished IL-1 and tumour necrosis factor (TNF)-a-induced expression of ICAM-1 and E-selectin in vitro [25]. However, long-term incubation of endothelial cells with glucocorticoids and TNF-a does not affect ICAM-1 expression [26,27].…”

Neutrophil trafficking into inflamed joints in patients with rheumatoid arthritis, and the effects of methylprednisolone

“…This strongly suggests that a treatment such as MP can rapidly and dramatically alter either the synovial membrane (by affecting the expression of cell-adhesion molecules on the vascular endothelium or of cytokines in the synovial membrane) and/or the synovial fluid (by affecting neutrophi1 chemotactic and activating factors). Glucocorticoids have been reported to inhibit the in vitro production of a number of proinflammatory cytokines (21)(22)(23)(24) and cell adhesion molecules (25,26), which may be important in mediating the inhibition of neutrophil trafficking. Serial studies of the synovial membrane and synovial fluid will be required to dissect out these important effects, and are currently being pursued by this group.…”

The adhesion molecules of inflammation

“…Thus, diminished adhcsivencss of the endothelium for Ieukocytcs rnay play a role in the antiinflammatory mechanism of corticosteroids. It most likcly explains the lcukocytosis of steroid therapy and the diminished resistance to infcction of patients treated with these agents (92).…”