Peripheral injection of bacterial endotoxin lipopolysaccharide (LPS) induces brain mRNA expression of the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha and the cytokine-responsive immediate-early gene IkappaBalpha. Peripheral LPS also increases levels of plasma glucocorticoids. Whether the induction of IkappaBalpha mRNA in the brain after peripheral LPS injection is caused by the feedback action of glucocorticoids has not been determined. In this study, we examined the mRNA expression of IkappaBalpha and IL-1beta in the rat brain by in situ hybridization histochemistry. Injection of the glucocorticoid agonist dexamethasone induced IkappaBalpha mRNA expression in the brain in a pattern identical to that of LPS injection. LPS but not dexamethasone also induced IL-1beta mRNA expression. Pretreatment with dexamethasone 30 min before LPS injection enhanced the expression of IkappaBalpha mRNA in the brain in a dose-dependent manner. Immobilization of rats for 2 hr (which raises glucocorticoid levels) also induced IkappaBalpha mRNA expression without inducing the expression of IL-1beta. Brain IkappaBalpha expression induced by peripheral LPS injection was attenuated by pretreatment of rats with the glucocorticoid antagonist RU-486. Finally, increased expression of IL-1beta mRNA in the brain was observed at 4 hr after peripheral LPS injection in adrenalectomized rats compared with sham-operated rats. These results reveal that in the brain glucocorticoids selectively induce IkappaBalpha mRNA expression, which serves as a negative feedback mechanism for peripheral LPS-induced synthesis of proinflammatory cytokines. Such an inhibitory control mechanism may be important for preventing prolonged expression of proinflammatory cytokines in the brain after peripheral immune challenge.