Synergy between tumor necrosis factor alpha and interleukin-1 in the induction of sickness behavior in mice

Like interleukin-1, recombinant human tumor necrosis factor alpha (TNF alpha) has been found to decrease social exploration and induce weight loss in mice in a dose and time-dependent manner. The present study was carried out to study the interaction between these two cytokines. Mice were injected IP with subthreshold doses of TNF alpha (2.5 micrograms/mouse) and IL-1 beta (50 ng/mouse). Social exploration was decreased 2 and 4 h after injection of TNF and IL-1, but body weight was not affected. Subthreshold doses of TNF alpha (90 ng/mouse) and IL-1 beta (100 pg/mouse) were also injected intracerebroventricularly (ICV). Social exploration was decreased 1.5 and 3 h after injections of the two cytokines and body weight was decreased for 6 h. To test the possibility of central induction of IL-1 by TNF alpha, mice pretreated with IL-1 receptor antagonist (IL-1ra, 1.8 micrograms/mouse, ICV) were injected with 90 ng TNF alpha. Pretreatment with IL-1ra antagonized the depressive effect of TNF alpha on behavior, but had no effect on weight loss induced by this cytokine. These results suggest that TNF alpha-induced behavioral alterations are mediated by endogenously released IL-1, whereas metabolic changes are dependent on the release of other cytokines.