CHARACTERIZATION OF EARLY CYTOKINE RESPONSES AND AN INTERLEUKIN (IL)-6-DEPENDENT PATHWAY OF ENDOGENOUS GLUCOCORTICOID INDUCTION DURING MURINE CYTOMEGALOVIRUS-INFECTION

Early infection with murine cytomegalovirus (MCMV) induces circulating levels of interleukin (IL)-12, interferon (IFN)-gamma, and tumor necr osis factor (TNF). Studies presented here further characterize these r esponses by defining kinetics and extending evaluation to include IL-1 , IL-6, and glucocorticoids. IL-12 p40, IFN-gamma, TNF, IL-1 alpha, an d IL-6 were shown to be increased, but IL-1 beta was undetectable, in serum of MCMV-infected mice. The IL-12 p40, IFN-gamma, TNF, and IL-6 r esponses were dramatic with peak levels reaching >150-10,000 pg/ml at 32-40 h alter infection and rapidly declining thereafter. Glucocortico id induction, peaking at 36 h and reaching 30-fold increases above con trol values, accompanied the cytokine responses. Mice with cytokine de ficiencies or neutralized cytokine function demonstrated that IL-6 was the pivotal mediator of the glucocorticoid response, with IL-1 contri buting to IL-6 production. The IL-6 requirement appeared to be specifi c for virus-type stimuli as the synthetic analogue of viral nucleic ac id, polyinosinic-polycytidylic acid, also induced IL-6-dependent gluco corticoid release, but treatments with the bacterial product lipopolys accharide and a non-immune physical restraint stressor elicited IL-6-i ndependent responses. Collectively, the results identify IL-6 as a pri mary mediator of glucocorticoid induction, and elucidate specific path ways of interactions between immune and neuroendocrine systems during viral infection.