1185 J. Exp. Med.  The R ockefeller University Press • 0022-1007/ 97/ 04/ 1185/ 08 $2.00 Volume 185, Number 7, April 7, 1997 1185–1192 Characterization of Early Cytokine Responses and an Interleukin (IL)-6–dependent Pathway of Endogenous Glucocorticoid Induction during Murine Cytomegalovirus Infection By Melanie C. R uzek,* Andrew H. Miller, ‡ Steven M. O pal,* Bradley D. Pearce, ‡ and Christine A. Biron* From the *Division of Biology and Medicine, Brown University, Providence, R hode Island 02912; and ‡ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, A tlanta, Georgia 30322 Summary Early infection with murine cytomegalovirus (MCMV) induces circulating levels of interleukin (IL)-12, interferon (IFN)- , 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- , TNF, IL-1, and IL-6 were shown to be increased, but IL-1 was undetectable, in serum of MCMV-infected mice. The IL-12 p40, IFN- , 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. T he cytokines IL-12, IFN- , TNF, IL-1, and IL-6 are in- duced under conditions of sepsis with gram-negative bacteria and in response to administration of the gram-neg- ative bacterial product endotoxin, i.e., LPS (1, 2). High levels of these cytokines contribute to pathologies charac- terized as endotoxin-induced shock with wasting, thymic atrophy, and life-threatening states (1–3). Circulating TNF, IL-1, and/ or IL-6, elicited as a cascade after exposure to LPS (4–6) or after administration of purified cytokines (7), induce the steroid hormones glucocorticoids. Induction is largely a result of hypothalamic-pituitary-adrenal (HPA) 1 axis activation through stimulating hypothalamus production of corticotropin-releasing hormone (CR H), which induces pi- tuitary release of adrenocorticotropin hormone (ACTH) for stimulation of adrenal gland glucocorticoid production. Glucocorticoids can suppress multiple immune functions, in- cluding cytokine production and T cell responses (4, 8, 9). Thus, the immune and neuroendocrine systems can com- municate to provide feedback inhibition mechanisms limit- ing immune responses. In addition to stimulation as a result of cytokine re- sponses to bacterial LPS, glucocorticoid release through the HPA axis occurs as part of circadian rhythm (10) and is in- duced by a variety of other stimuli including physical or cognitive stress (11), a synthetic analogue for viral nucleic acids, i.e., polyinosinic-polycytidylic acid (poly I:C) (12), and turpentine induction of inflammation (3, 13). The pre- cise pathways for HPA axis activation under each of these conditions has yet to be fully elucidated, and little is known about endogenous induction in response to infections. If glucocorticoids are elicited during challenge with patho- gens, they may shape or modulate down-stream T cell functions as well as control acute detrimental cytokine- mediated pathologies (4, 8, 9). This laboratory has been examining cytokine responses and functions during viral infections (14–16). In particular, responses to infections of mice with the cytopathic (14–18) murine cytomegalovirus (MCMV) are being investigated. 1 A bbreviations used in this paper: ACTH, adrenocorticotropin hormone; CR H, corticotropin-releasing hormone; HPA, hypothalamic-pituitary- adrenal; MCMV, murine cytomegalovirus; NDV, Newcastle disease vi- rus; poly I:C, polyinosinic-polycytidylic acid. on June 25, 2015 jem.rupress.org Downloaded from Published April 7, 1997