Glucocorticoids inhibit the autoregulatory induction of interleukin-1 in monocytes after endotoxin stimulation

Interleukin-1 (IL-1) is an important mediator in the mechanisms underlying the immune and inflammatory responses. It has pleiotropic effects in host defense and, when present in high concentrations, participates in the development of pathological processes. IL-1 is the most potent cytokine in the activation of the hypothalamic-pituitary-adrenal axis during infection and therefore leads to a glucocorticoid increase. Glucocorticoids in a feedback loop inhibit the production of IL-1 induced by endotoxin. IL-1 also induces its own synthesis. In this report, we examine the role of glucocorticoids in the regulation of IL-1 autoregulatory induction in human monocytes at the level of IL-1 protein production and mRNA accumulation. Using recombinant IL-1 receptor antagonist we established that endogenously produced IL-1 affects induction of IL-1beta protein by lipopolysaccharide (LPS) at the level of mRNA expression. The inhibition of LPS-stimulated IL-1beta production and mRNA expression by glucocorticoids (dexamethasone and cortisol) reaches the same level with glucocorticoids alone or in combination with rIL-1ra. IL-1beta mRNA induced by exogenously added IL-1beta was also inhibited by glucocorticoids. These results indicate that glucocorticoids inhibit the autoregulatory loop of IL-1 in LPS-stimulated monocytes and constitute a mechanism for controlling IL-1 feedback stimulation.