Endogenous glucocorticoids protect against cytokine-mediated lethality during viral infection

Certain cytokines activate the hypothalamic-pituitary-adrenal axis for gluc ocorticoid release, and these hormones can protect against cytokine-mediate d pathologies. However, endogenous activation of such a pathway has not bee n established during infections, A prominent glucocorticoid response peaks 36 h following murine CMV (MCMV) infection, coincident with circulating lev els of the cytokines IL-12, IFN-gamma, TNF, and IL-6, and dependent on IL-6 fur maximal release. These studies examined functions of the hormone induc tion. Mice rendered glucocorticoid deficient by adrenalectomy were more sus ceptible than intact mice to MCMV-induced lethality, and the increased sens itivity was reversed by hormone replacement, Lack of endogenous glucocortic oids resulted in increases in IL-12, IFN-gamma, TNF, and IL-6 production, a s well as in mRNA expression for a wider range of cytokines, also including IL-1 alpha and IL-1 beta, Viral burdens did not increase, and actually dec reased, in the livers of glucocorticoid-deficient mice, TNF, but not lFN-ga mma, was required for increased lethality in the absence of endogenous horm one. These results conclusively demonstrate the importance of induced endog enous glucocorticoids in protection against life-threatening effects result ing from infection-elicited cytokine responses, Taken together with the dep endence on induced IL-6, they document existence of an immune system-hypoth alamic-pituitary-adrenal axis pathway for regulating endogenous responses t o viral infections.