CHRONIC STIMULATION OF THE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS IN RATS BY INTERLEUKIN-1-BETA - CENTRAL AND PERIPHERAL MECHANISMS

The authors have studied mechanisms which could be involved in the sus tained activation of the hyp othalamus-pituitary-adrenal (HPA) axis du ring continuous infusion of rats with recombinant human interleukin-1 beta (IL-1 beta). First, the effects of 3 days of intracerebroventricu lar (i.c.v.) infusion of rats with IL-1 on plasma adrenocorticotropin (ACTH) and corticosterone (B) levels were investigated, Thereafter, ch anges in plasma ACTH and B levels were followed in rats intraperitonea lly (i.p.) infused with IL-1 beta after immunoneutralization of cortic otropin-releasing hormone (CRH), hypophysectomy (HPX), macrophage depl etion using dichloromethylene diphosphonate (Cl(2)MDP)-containing lipo somes, adrenalectomy (ADX) and dexamethasone (DEX) administration, res pectively, Infusion of IL-1 beta i.c.v., even in doses as low as 0.1 m u g/day, induced significant increases in plasma ACTH and B levels, HP X and ADX rats died within 18 h after starting the IL-1 beta infusion (0.5 mu g/day). Immunoneutralization of CRH significantly decreased an d macrophage depletion significantly increased the stimulation of the HPA axis by IL-1 (4.0 mu g/day). Administration of high doses of DEX c ompletely abolished the stimulation of the HPA axis by IL-1 beta (2.0 beta g/day). The present study demonstrates that lower doses of IL-1 b eta were able to activate the HPA axis when infused i.c.v. compared wi th i.p. Regarding stimulation of the HPA axis by chronic i.p. infusion of IL-1 beta the present study: (1) provides evidence that the CRH sy stem is involved; (2) provides no evidence for a direct stimulatory ef fect of IL-1 beta on the release of B by the adrenal gland which is of suffcient magnitude to resist the stress of chronic i.p. IL-1 beta in fusion; (3) shows that endogenous macrophage-derived mediators, induce d by i.p. IL-1 beta infusion, express an overall inhibitory rather tha n a stimulatory effect on the activity of the HPA axis; (4) demonstrat es that exogenous administration of DEX blocks the effect of IL-1 beta , which fits well in the concept of an immunoregulatory feedback betwe en IL-1 beta and glucocorticoids.