GLUCOCORTICOIDS SUPPRESS INTERLEUKIN-1 RECEPTOR ANTAGONIST SYNTHESIS FOLLOWING INDUCTION BY ENDOTOXIN

Glucocorticoids, as part of their physiological role in the control of inflammatory and immune processes, suppress the expression of IL-1 an d other cytokines. We have found a dose-dependent inhibition by dexame thasone (10 nM to 10 mu M) of mRNA levels of the recently cloned IL-1 receptor antagonist (IL-1ra) in endotoxin-stimulated human monocytes. At the same concentrations, both dexamethasone and cortisol inhibited the secretion of IL-1ra. These inhibitory effects were reversed by blo cking glucocorticoid receptors with the specific antagonist RU 38486, but not by adding exogenous IL-1, even up to 100 ng/ml, to the monocyt es. A similar inhibition of IL-1ra mRNA and protein secretion was foun d in monocytes obtained after dexamethasone administration in vivo. In addition, we observed parallel increases in glucocorticoid and IL-1ra levels following endotoxin administration to normal volunteers. Our r esults show that glucocorticoids shut down not only IL-1 but also IL-1 ra expression, ruling out induction of IL-1ra as part of the glucocort icoid antiinflammatory mechanism. The control of the delicate immunore gulatory balance of the IL-1/IL-1ra system during endotoxemia undersco res the physiological importance of glucocorticoids in the final contr ol of immune responses.