ANOREXIA INDUCED BY CYTOKINE INTERACTIONS AT PATHOPHYSIOLOGICAL CONCENTRATIONS

Interleukin (IL)-1 beta, IL-8, and tumor necrosis factor-alpha (TNF-al pha) induce anorexia when administered intracerebroventricularly at do ses that yield estimated pathophysiological concentrations reported in the cerebrospinal fluid (CSF). Our hypothesis is that pivotal cytokin es released during pathological processes interact to induce anorexia during disease. In the present study, we investigated the effects of t he intracerebroventricular microinfusion of individual or multiple com binations (8 dyads and 5 triads) of IL-1 beta, IL-8, and TNF-alpha on feeding and the microstructure of eating in rats maintained ad libitum . Estimated pathophysiological concentrations of cytokine combinations exhibited additive or synergistic activities in inducing anorexia. Co mputerized analysis of behavioral patterns demonstrated that the most effective treatment (triad of 1.0 ng IL-1 beta + 20 ng IL-8 + 20 ng TN F-alpha/rat, n = 11) decreased nighttime meal size by 42% and feeding rate (meal size/meal duration) by 26%, whereas it increased the satiet y ratio (postprandial intermeal intervals/meal size) by 80%; meal dura tion and meal frequency were not significantly affected. Analysis of m eal parameters in 4-h intervals revealed a maximum effect during the f irst 4-h interval after the intracerebroventricular ar administration. The time course during this initial 4-h interval analyzed in 10-min p eriods was similar for IL-8 (n = 10) and TNF-alpha (n = 11), and both were significantly different from the time course induced by IL-1 beta (n = 10) and the most effective triad (n = 11). Intracerebroventricul ar microinfusion of heat-inactivated triad or intraperitoneal administ ration of the most effective triad, in doses equivalent to those admin istered centrally, had no effect on feeding. The results suggest that estimated pathophysiological concentrations of cytokines in the CSF ac t centrally and additively or synergistically to decrease feeding, and this effect may participate in the anorexia frequently accompanying p athological processes.