Glucocorticoids, as a part of their physiological role in the control of inflammatory and immune processes, suppress the expression of interleukin-1 (IL-1) and other cytokines. Human monocyte IL-1 receptor antagonist (IL-1ra) messenger ribonucleic acid (mRNA) expression and protein secretion are inhibited by dexamethasone. We have now further studied the regulation of IL-1ra by the major physiological human glucocorticoid, cortisol. We found that cortisol incubation induced a decrease in IL-1ra mRNA expression and a significant inhibition of IL-1ra protein secretion in cell cultures of human peripheral monocytes stimulated with the bacterial endotoxin lipopolysaccharide (LPS). Oral administration of 276 mumol cortisol to normal subjects also decreased LPS-induced IL-1ra synthesis in cultured monocytes. By coincubating the monocytes with either the mineralocorticoid antagonist spironolactone or the glucocorticoid receptor antagonist RU 38486, the in vitro cortisol-induced inhibition of LPS-stimulated IL-1ra secretion was partially reversed. The mineralocorticoid aldosterone exerted a significant decrease in LPS-induced monocyte IL-1ra secretion in vitro, which was blocked by coincubation with spironolactone. In addition, the expression of mineralocorticoid receptor mRNA in human monocytes was observed by PCR of reversed transcribed RNA. Our results further indicate that corticosteroids physiologically control the IL-1/IL-1ra system during inflammatory or immune processes. Moreover, we provide evidence that, in addition to a glucocorticoid receptor-mediated effect, the mineralocorticoid receptor is involved in the inhibition of monocyte IL-1ra secretion by cortisol.