1154 Chronic Il - 1 Infusion and the Hpa Axis

It has been shown that acute administration of interleukin-1 (IL-1 ) to rats elicits a transitory increase in plasma ACTH and corticosterone (B) levels. To investigate the effects of chronic administration of IL-1 on plasma ACTH and B levels, in the present study rats were equipped with Alzet osmotic minipumps loaded with either IL-1 (delivery rate 0.5, 2.0, or 4.0 fig/ 24 h, ip, for 1 week) or saline. At the end of the treatment the rats were decapitated, the adrenals were weighed, and the in vitro release of 0-endorphin (0E) by the anterior pituitary and that of B by the adrenal gland were measured. Continuous administration of 2.0 and 4.0 fig IL-1/24 h resulted in a persistent increase in plasma ACTH and B concentrations compared to the levels in saline-infused rats, with peak levels on the first day of administration. In addition, adrenal weights of IL-1 rats were significantly higher than those of saline rats. The 4.0-fig IL-1/ day in vivo treatment induced an increase in spontaneous in vitro secretion of (3E and B, while the in vitro responses of the S UBSTANTIAL evidence has now accumulated that there is a functional relationship between the im­ mune and the (neuro)endocrine system. Interleukin-1 (IL-1), a pleiotropic polypeptide synthesized and released predominantly by macrophages, acts as a primary media­ tor of the acute phase response to microbial invasion and physical stressors (1, 2). In addition to its role in the coordination of host defense mechanisms, IL-1 is thought to serve as a trigger for the activity of the hypothalamopituitary-adrenal (HPA) axis, which is chronically stim­ ulated under these conditions (3-5). Evidence for this idea is primarily based on in vivo experiments in laboratory animals. It has been shown Received October 10, 1991. Address all correspondence and requests for reprints to: C. G. J. Sweep, Department of Medicine, Division of Endocrinology, St. Rad­ boud Hospital, Geert Grooteplein zuid 8, 6500 HB Nijmegen, The Netherlands. * This work was supported by the Royal Netherlands Academy of Arts and Sciences. pituitary (to CRF) and the adrenal (to ACTH) of animals treated in vivo with IL-1 were significantly diminished. IL-1 at a dose of 0.5 fig failed to affect plasma ACTH and B values, adrenal weight, and in vitro (3E and B secretion. Chronic infusion of rats with 4.0 fig IL-l/day induced prolonged fever, whereas at lower doses of IL-1 (2.0 and 0.5 fig), temperatures were elevated only on the first 2 days of infusion. IL-1 at doses of 2.0 and 4.0 fig/ day induced suppression of body weight gain on the first 2 days of the treatment period compared to saline treatment. Plasma norepinephrine and/or epinephrine concentrations were raised only on day 1 of the 2.0and 4.0-fig IL-1 experiments. Thus, the observed effects of IL-1 on the hypothalamo-pituitary-adrenal axis probably do not result merely from stress induced by the treatment. Taken together, our data show the potential of IL-1 to induce a dose-dependent and long term activation of the pituitary-adrenal axis. (Endocrinology 130: 1153-1164, 1992) that acute administration of IL-1 activates the HPA axis in mice and rats, as manifested by increased levels of ACTH and/or corticosterone (B) in plasma (3, 6-8). Whether IL-1 can directly act at the pituitary and/or adrenal level to release ACTH and B, respectively, is still controversial. Strong evidence exists that the brain is the primary site of action, and that IL-1, either directly or indirectly, acts at the level of the hypothalamus by stimulation of CRF release (6, 7, 9-12). In these studies IL-1 was administered as a single bolus injection in relatively high doses, and plasma levels of ACTH and/ or B were followed for only a few hours. IL-1 has been shown to induce fever (13), to inhibit food intake (1416), and, in high doses, to be toxic to the animal (17). Little or no attention has been given in studies on the effects of IL-1 on the HPA axis to the question of whether these effects resulted from a direct action of IL1 on the HPA axis or were secondary to stress effects induced by IL-1 administration.