Anorexia induced by chronic central administration of cytokines at estimated pathophysiological concentrations

Interleukin-1 beta (IL-1 beta), IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) induce acute anorexia by direct action in the central nervous system (CNS) at estimated pathophysiological concentrations reported in the cerebrospinal fluid (CSF). Cytokine-induced anorexia may also participate in the long-term anorexia observed during disease. Here, we studied the effects of chronic intracerebroventricular (ICV) microinfusion (through osmotic minipumps) of various cytokines on feeding and drinking in rats. The results show: IL-1 beta decreased nighttime feeding dose-dependently (with 0.5, 1.0, 2.0 and 8.0 ng/24 h, n > or = 8/group). The decrease of feeding and corresponding decrease of body weight persisted during the 7-day infusion. Total daily food intake decrease was less prominent relative to the nighttime decrease because daytime food intake slightly increased. Feeding and body weight increased toward baseline following the end of the IL-1 beta infusion. ICV microinfusion of heat-inactivated IL-1 beta or IL-1 beta plus IL-1 receptor antagonist had no effect, suggesting specificity of action of IL-1 beta. Water intake did not decrease in any IL-1 beta-treated group, suggesting specificity on feeding. Chronic ICV administration of TNF-alpha (20, 100, or 300 ng/24 h), IL-6 (100 ng/24 h), or IL-8 (20 ng/24 h) was significantly less effective than IL-1 beta in inducing behavioral modifications. The results suggest that IL-1 beta, at doses that yield estimated pathophysiological concentrations in the CSF, is capable of inducing long-term anorexia and this effect may participate in the anorexia observed during chronic disease.