DEFECTIVE INTERLEUKIN-1-INDUCED ACTH RELEASE IN CHOLESTATIC RATS - IMPAIRED HYPOTHALAMIC PGE(2) RELEASE

A complete regulatory loop exists between the immune and neuroendocrin e systems. Proinflammatory mediators such as endotoxin (lipopolysaccha ride) and interleukin-1 (IL-1) are capable of activating the hypothala mic-pituitary-adrenal (HPA) axis at the hypothalamic level, presumably by inducing the synthesis of prostaglandins. We have recently identif ied abnormalities in the stress-induced activation of the HPA axis in cholestatic rats. Therefore, in rats with cholestasis due to bile duct resection and sham-resected controls, we studied alterations in proin flammatory mediator-induced activation of the HPA axis and documented the role of alterations in hypothalamic prostaglandin synthesis in the se abnormalities. Systemic administration of endotoxin and IL-1 result ed in a significant attenuation of adrenocorticotropic hormone (ACTH) release into plasma in bile duct-resected compared with sham-resected animals. This suppression of endotoxin- or IL-1-induced ACTH release i n bile duct-resected rats was associated with a complete absence of IL -1-induced hypothalamic release of prostaglandin E(2) (PGE(2)) in vitr o in these animals. In contrast, sham-resected rats exhibited a 70% in crease in hypothalamic PGE(2) secretion in vitro in response to IL-1. However, bile duct-resected rats exhibited HPA axis activation similar to that of sham-resected animals in response to intracerebroventricul arly infused PGE(2). Therefore, cholestasis in the rat is associated w ith an attenuation of central activation of the HPA axis by proinflamm atory mediators that appears to be mediated, at least in part, by defe ctive IL-1-induced hypothalamic prostaglandin production.