Endogenous glucocorticoids protect against cytokine-mediated lethality during viral infection.
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.
Ruzek
M C
MC
Department of Molecular Microbiology and Medicine, Brown University, Providence, RI 02912, USA.
Pearce
B D
BD
Miller
A H
AH
Biron
C A
CA
D000284:Administration, Oral; D000315:Adrenalectomy; D000818:Animals; D003345:Corticosterone / Q000008:administration & dosage / Q000494:pharmacology; D016207:Cytokines / Q000009:adverse effects* / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005938:Glucocorticoids / Q000502:physiology*; D006566:Herpesviridae Infections / Q000276:immunology* / Q000401:mortality* / Q000517:prevention & control / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000254:growth & development / Q000276:immunology*; D016019:Survival Analysis
D016207:Cytokines; D005938:Glucocorticoids; D003345:Corticosterone