Induction of I kappa B alpha mRNA expression in the brain by glucocorticoids: A negative feedback mechanism for immune-to-brain signaling

Peripheral injection of bacterial endotoxin lipopolysaccharide (LPS) induce s brain mRNA expression of the proinflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha and the cytokine-responsive im mediate-early gene I kappa B alpha. Peripheral LPS also increases levels of plasma glucocorticoids. Whether the induction of I kappa B alpha mRNA in t he brain after peripheral LPS injection is caused by the feedback action of glucocorticoids has not been determined. In this study, we examined the mR NA expression of I kappa B alpha and IL-1 beta in the rat brain by in situ hybridization histochemistry. Injection of the glucocorticoid agonist dexam ethasone induced I kappa B alpha mRNA expression in the brain in a pattern identical to that of LPS injection. LPS but not dexamethasone also induced IL-1 beta mRNA expression. Pretreatment with dexamethasone 30 min before LP S injection enhanced the expression of I kappa B alpha mRNA in the brain in a dose-dependent manner. Immobilization of rats for 2 hr (which raises glu cocorticoid levels) also induced I kappa B alpha mRNA expression without in ducing the expression of IL-1 beta. Brain I kappa B alpha expression induce d by peripheral LPS injection was attenuated by pretreatment of rats with t he glucocorticoid antagonist RU-486. Finally, increased expression of IL-1 beta mRNA in the brain was observed at 4 hr after peripheral LPS injection in adrenalectomized rats compared with sham-operated rats. These results re veal that in the brain glucocorticoids selectively induce I kappa B alpha m RNA expression, which serves as a negative feedback mechanism for periphera l LPS-induced synthesis of proinflammatory cytokines. Such an inhibitory co ntrol mechanism may be important for preventing prolonged expression of pro inflammatory cytokines in the brain after peripheral immune challenge.