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*
Department of Molecular Microbiology and Medicine, Division of Biology and Medicine, Brown University, Providence, RI 02912; and
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322
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-
, 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-,
TNF, and IL-6 production, as well as in mRNA expression for a wider
range of cytokines, also including IL-1
and IL-1ß. Viral burdens
did not increase, and actually decreased, in the livers of
glucocorticoid-deficient mice. TNF, but not IFN-, 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.
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