Endogenous Glucocorticoids Protect Against Cytokine-Mediated Lethality During Viral Infection

• Published in: The Journal of immunology (1950) 1999-03, Vol.162 (6), p.3527-3533
• Main Authors: Ruzek, Melanie C, Pearce, Bradley D, Miller, Andrew H, Biron, Christine A
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adrenalectomy; Animals; Corticosterone - administration & dosage; Corticosterone - pharmacology; Cytokines - adverse effects; Cytokines - antagonists & inhibitors; Cytokines - biosynthesis; Glucocorticoids - physiology; Herpesviridae Infections - immunology; Herpesviridae Infections - mortality; Herpesviridae Infections - prevention & control; Herpesviridae Infections - virology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Murine cytomegalovirus; Muromegalovirus - growth & development; Muromegalovirus - immunology; Survival Analysis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.162.6.3527

Certain cytokines activate the hypothalamic-pituitary-adrenal axis for glucocorticoid release, and these hormones can protect against cytokine-mediated pathologies. However, endogenous activation of such a pathway has not been established during infections. A prominent glucocorticoid response peaks 36 h following murine CMV (MCMV) infection, coincident with circulating levels of the cytokines IL-12, IFN-gamma, TNF, and IL-6, and dependent on IL-6 for maximal release. These studies examined functions of the hormone induction. Mice rendered glucocorticoid deficient by adrenalectomy were more susceptible than intact mice to MCMV-induced lethality, and the increased sensitivity was reversed by hormone replacement. Lack of endogenous glucocorticoids resulted in increases in IL-12, IFN-gamma, TNF, and IL-6 production, as 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 decreased, in the livers of glucocorticoid-deficient mice. TNF, but not IFN-gamma, was required for increased lethality in the absence of endogenous hormone. These results conclusively demonstrate the importance of induced endogenous glucocorticoids in protection against life-threatening effects resulting from infection-elicited cytokine responses. Taken together with the dependence on induced IL-6, they document existence of an immune system-hypothalamic-pituitary-adrenal axis pathway for regulating endogenous responses to viral infections.