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 sustained activation of the hyp othalamus-pituitary-adrenal (HPA) axis during continuous infusion of rats with recombinant human interleukin-1 beta (IL-1 beta). First, the effects of 3 days of intracerebroventricular (i.c.v.) infusion of rats with IL-1 on plasma adrenocorticotropin (ACTH) and corticosterone (B) levels were investigated, Thereafter, changes in plasma ACTH and B levels were followed in rats intraperitoneally (i.p.) infused with IL-1 beta after immunoneutralization of corticotropin-releasing hormone (CRH), hypophysectomy (HPX), macrophage depletion using dichloromethylene diphosphonate (Cl(2)MDP)-containing liposomes, adrenalectomy (ADX) and dexamethasone (DEX) administration, respectively, Infusion of IL-1 beta i.c.v., even in doses as low as 0.1 mu g/day, induced significant increases in plasma ACTH and B levels, HPX and ADX rats died within 18 h after starting the IL-1 beta infusion (0.5 mu g/day). Immunoneutralization of CRH significantly decreased and macrophage depletion significantly increased the stimulation of the HPA axis by IL-1 (4.0 mu g/day). Administration of high doses of DEX completely 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 beta were able to activate the HPA axis when infused i.c.v. compared with 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 system is involved; (2) provides no evidence for a direct stimulatory effect 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 infusion; (3) shows that endogenous macrophage-derived mediators, induced by i.p. IL-1 beta infusion, express an overall inhibitory rather than a stimulatory effect on the activity of the HPA axis; (4) demonstrates that exogenous administration of DEX blocks the effect of IL-1 beta, which fits well in the concept of an immunoregulatory feedback between IL-1 beta and glucocorticoids.