The direct effect of the endogenous glucocorticoid (GC) hydrocortisone (HC) on interleukin-6 (IL-6) production was examined using purified populations of human peripheral blood monocytes (Mo). Lipopolysaccharide (LPS) induced IL-6 production by Mo in a dose-dependent fashion. IL-6 was detected in Mo supernatants as early as 2 hr after stimulation, with peak IL-6 production observed by 16 hr. Simultaneous addition of HC and LPS resulted in a significant decrease of IL-6 production 4 hr after LPS treatment, with maximum inhibition observed at 16-24 hr. An attenuation of the inhibitory effect of HC occurred with greater concentrations of LPS and with the delay of HC addition until after LPS. However, there was no correlation between the quantity of IL-6 produced by Mo and the level of HC inhibition. The inhibitory effect of HC was greater if LPS, rather than IL-1 beta, were used as a stimulus to induce IL-6 production. The EC50 of LPS-induced IL-6 production by HC was 2.0 x 10(-7) M. The inhibitory effect of HC on LPS-stimulated IL-6 production was GC specific and receptor mediated because: (i) equivalent inhibition was not observed with other endogenous steroids and (ii) equimolar amounts of the GC antagonist RU 486 blocked the GC-mediated effect.