INHIBITION OF LIPOPOLYSACCHARIDE-INDUCED MONOCYTE INTERLEUKIN-1 RECEPTOR ANTAGONIST SYNTHESIS BY CORTISOL - INVOLVEMENT OF THE MINERALOCORTICOID RECEPTOR

Glucocorticoids, as a part of their physiological role in the control of inflammatory and immune processes, suppress the expression of inter leukin-1 (IL-1) and other cytokines. Human monocyte IL-1 receptor anta gonist (IL-1ra) messenger ribonucleic acid (mRNA) expression and prote in secretion are inhibited by dexamethasone. We have now further studi ed the regulation of IL-1ra by the major physiological human glucocort icoid, cortisol. We found that cortisol incubation induced a decrease in IL-1ra mRNA expression and a significant inhibition of IL-1ra prote in secretion in cell cultures of human peripheral monocytes stimulated with the bacterial endotoxin lipopolysaccharide (LPS). Oral administr ation of 276 mu mol cortisol to normal subjects also decreased LPS-ind uced IL-1ra synthesis in cultured monocytes. By coincubating the monoc ytes with either the mineralocorticoid antagonist spironolactone or th e glucocorticoid receptor antagonist RU 38486, the in vitro cortisol-i nduced inhibition of LPS-stimulated IL-1ra secretion was partially rev ersed. The mineralocorticoid aldosterone exerted a significant decreas e in LPS-induced monocyte IL-1ra secretion in vitro, which was blocked by coincubation with spironolactone. In addition, the expression of m ineralocorticoid receptor mRNA in human monocytes was observed by PCR of reverse transcribed RNA. Our results further indicate that corticos teroids physiologically control the IL-1/IL-1ra system during inflamma tory or immune processes. Moreover, we provide evidence that, in addit ion to a glucocorticoid receptor-mediated effect, the mineralocorticoi d receptor is involved in the inhibition of monocyte IL-1ra secretion by cortisol.