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© The Rockefeller University Press, 0022-1007/1997/4/1185/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 7, April 7, 1997 1185-1192

Article

Characterization of Early Cytokine Responses and an Interleukin (IL)-6–dependent Pathway of Endogenous Glucocorticoid Induction during Murine Cytomegalovirus Infection

Melanie C. Ruzek*, Andrew H. Miller{ddagger}, Steven M. Opal*, Bradley D. Pearce{ddagger}, and Christine A. Biron*

From the * Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912; and {ddagger} Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322

Early infection with murine cytomegalovirus (MCMV) induces circulating levels of interleukin (IL)-12, interferon (IFN)-{gamma}, and tumor necrosis factor (TNF). Studies presented here further characterize these responses by defining kinetics and extending evaluation to include IL-1, IL-6, and glucocorticoids. IL-12 p40, IFN-{gamma}, TNF, IL-1{alpha}, and IL-6 were shown to be increased, but IL-1β was undetectable, in serum of MCMV-infected mice. The IL-12 p40, IFN-{gamma}, TNF, and IL-6 responses were dramatic with peak levels reaching >150–10,000 pg/ml at 32–40 h after infection and rapidly declining thereafter. Glucocorticoid induction, peaking at 36 h and reaching 30-fold increases above control values, accompanied the cytokine responses. Mice with cytokine deficiencies or neutralized cytokine function demonstrated that IL-6 was the pivotal mediator of the glucocorticoid response, with IL-1 contributing to IL-6 production. The IL-6 requirement appeared to be specific for virus-type stimuli as the synthetic analogue of viral nucleic acid, polyinosinic-polycytidylic acid, also induced IL-6–dependent glucocorticoid release, but treatments with the bacterial product lipopolysaccharide and a non-immune physical restraint stressor elicited IL-6–independent responses. Collectively, the results identify IL-6 as a primary mediator of glucocorticoid induction, and elucidate specific pathways of interactions between immune and neuroendocrine systems during viral infection.

Address correspondence to Christine A. Biron, Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Box G-B618, Brown University, Providence, RI 02912.

1 Abbreviations used in this paper: ACTH, adrenocorticotropin hormone; CRH, corticotropin-releasing hormone; HPA, hypothalamic-pituitaryadrenal; MCMV, murine cytomegalovirus; NDV, Newcastle disease virus; poly I:C, polyinosinic-polycytidylic acid.


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