BACKGROUND: Recent studies have raised the hypothesis that glucocorticoids could diminish the ability of endothelial cells to direct leukocyte traffic into inflamed tissues by inhibiting expression of the adhesion molecules endothelial-leukocyte adhesion molecule-1 and intercellular adhesion molecule-1. The aim of the present study was to investigate whether glucocorticoids also regulate the expression of L-selectin and CD11/CD18 integrins on human neutrophil granulocytes. METHODS AND RESULTS: Incubation of human whole blood with platelet-activating factor (PAF, 1 mumol/L) evoked downregulation of L-selectin and upregulation of CD11/CD18 adhesion receptors on neutrophils as measured by flow cytometry. While dexamethasone (0.1 nmol/L to 100 mumol/L) did not affect expression of adhesion molecules on resting neutrophils, it attenuated the PAF-induced changes in L-selectin and CD18 expression in a time- and concentration-dependent fashion with IC50 values of 31 and 13 nmol/L, respectively. These effects of dexamethasone were completely aborted by RU-486 (10 mumol/L), which blocks transcriptional activation of the glucocorticoid receptor, and by the protein synthesis inhibitor cycloheximide (35.5 mumol/L). Dexamethasone, up to a concentration of 1 mumol/L, neither affected significantly the release of granule enzymes nor interfered with PAF binding to its membrane receptors. CONCLUSIONS: Our results show that glucocorticoids at clinically relevant concentrations exert specific actions on expression of adhesion molecules on activated neutrophils, which are mediated through ligation of glucocorticoid receptors and induction of protein synthesis, and suggest a novel mechanism by which anti-inflammatory corticosteroids may inhibit leukocyte accumulation.
BACKGROUND: Recent studies have raised the hypothesis that glucocorticoids could diminish the ability of endothelial cells to direct leukocyte traffic into inflamed tissues by inhibiting expression of the adhesion molecules endothelial-leukocyte adhesion molecule-1 and intercellular adhesion molecule-1. The aim of the present study was to investigate whether glucocorticoids also regulate the expression of L-selectin and CD11/CD18 integrins on human neutrophil granulocytes. METHODS AND RESULTS: Incubation of human whole blood with platelet-activating factor (PAF, 1 mumol/L) evoked downregulation of L-selectin and upregulation of CD11/CD18 adhesion receptors on neutrophils as measured by flow cytometry. While dexamethasone (0.1 nmol/L to 100 mumol/L) did not affect expression of adhesion molecules on resting neutrophils, it attenuated the PAF-induced changes in L-selectin and CD18 expression in a time- and concentration-dependent fashion with IC50 values of 31 and 13 nmol/L, respectively. These effects of dexamethasone were completely aborted by RU-486 (10 mumol/L), which blocks transcriptional activation of the glucocorticoid receptor, and by the protein synthesis inhibitor cycloheximide (35.5 mumol/L). Dexamethasone, up to a concentration of 1 mumol/L, neither affected significantly the release of granule enzymes nor interfered with PAF binding to its membrane receptors. CONCLUSIONS: Our results show that glucocorticoids at clinically relevant concentrations exert specific actions on expression of adhesion molecules on activated neutrophils, which are mediated through ligation of glucocorticoid receptors and induction of protein synthesis, and suggest a novel mechanism by which anti-inflammatory corticosteroids may inhibit leukocyte accumulation.
Authors: D M H Cavalcanti; C M C Lotufo; P Borelli; Z S Ferreira; R P Markus; S H P Farsky Journal: Br J Pharmacol Date: 2007-11-05 Impact factor: 8.739
Authors: Jörg van den Boom; Marietta Wolter; Rork Kuick; David E Misek; Andrew S Youkilis; Daniel S Wechsler; Clemens Sommer; Guido Reifenberger; Samir M Hanash Journal: Am J Pathol Date: 2003-09 Impact factor: 4.307