Defective interleukin-1-induced ACTH release in cholestatic rats: impaired hypothalamic PGE2 release

Abstract

A complete regulatory loop exists between the immune and neuroendocrine systems. Proinflammatory mediators such as endotoxin (lipopolysaccharide) and interleukin-1 (IL-1) are capable of activating the hypothalamic-pituitary-adrenal (HPA) axis at the hypothalamic level, presumably by inducing the synthesis of prostaglandins. We have recently identified 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 proinflammatory mediator-induced activation of the HPA axis and documented the role of alterations in hypothalamic prostaglandin synthesis in these abnormalities. Systemic administration of endotoxin and IL-1 resulted 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 in bile duct-resected rats was associated with a complete absence of IL-1-induced hypothalamic release of prostaglandin E2 (PGE2) in vitro in these animals. In contrast, sham-resected rats exhibited a 70% increase in hypothalamic PGE2 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 intracerebroventricularly infused PGE2. Therefore, cholestasis in the rat is associated with an attenuation of central activation of the HPA axis by proinflammatory mediators that appears to be mediated, at least in part, by defective IL-1-induced hypothalamic prostaglandin production.

Liver-brain inflammation axis

“…Generally, in chronic inflammatory diseases that are associated with elevated proinflammatory cytokines (e.g., rheumatoid arthritis), hypoactivation of the HPA axis has been observed (36,98). Similar observations have also been made in experimental cholestasis (91,92,94).…”

“…In addition, reduced Fos expression in the hypothalamic PVN region in response to central administration of IL-1␤ has been demonstrated in cholestatic rodents, further supporting reduced neuronal activation in this region (92). Consistent with this observation, the increase in ACTH release typically observed in response to central IL-1␤ administration was markedly reduced in cholestatic rodents (94). CRH has been shown to have behavioral activating effects.…”

Suppression of the HPA axis during extrahepatic biliary obstruction induces cholangiocyte proliferation in the rat

“…Resection of the bile duct in rats leads to impaired stress-induced CRH release compared with controls, which results in decreased circulating ACTH levels (46,48). ACTH release from the pituitary as a result of IL-1␤ treatment is also dampened after bile duct resection (47). Furthermore, McNeilly et al (37) recently suggested that bile acid buildup as a result of cholestasis may have the ability to inhibit hepatic glucocorticoid clearance, thereby allowing glucocorticoid levels to increase to a level that would inhibit the HPA axis.…”

Fatigue in chronic disease

“…However, patients with RA fail to increase cortisol secretion following surgery, despite high circulating IL-1β levels, suggesting that a defect exists in the hypothalamic response to IL-1β in these patients [57]. In addition, rats with experimental cholestatic liver disease exhibit defective stimulation of ACTH release after the peripheral administration of IL-1β, consistent with abnormal hypothalamic CRH responsiveness to this cytokine in these animals [58].…”