To examine the role of interleukin-1beta (IL-1beta) in mediating sickness, we studied the effects of lipopolysaccharide (LPS) and IL-1beta on social behavior in endotoxin-responsive C3H/HeOuJ (OuJ) mice and endotoxin-resistant C3H/HeJ (HeJ) mice. Whereas LPS (1, 10 and 100 microg) depressed social behavior and body weight compared to saline in OuJ mice, in HeJ mice it did not. To determine if the refractoriness of HeJ mice to the behavioral effects of LPS was related to secretion of IL-1beta, in a second study, HeJ and OuJ mice were injected IP with LPS (10 microg) and plasma concentration of IL-1beta was determined postinjection. At 4 h postinjection, the plasma concentration of IL-1beta was increased by LPS in OuJ mice, but not in HeJ mice. The increase in plasma IL-1beta in OuJ mice corresponded to the maximal depression in social behavior. To further verify that HeJ mice are refractory to the behavioral effects of LPS because they fail to respond and produce cytokines, the social behavior of HeJ and OuJ mice injected IP with recombinant murine IL-1beta (0, 50, 100, or 200 ng) was compared. As anticipated, exogenous IL-1beta depressed social behavior similarly in endotoxin-responsive OuJ mice and endotoxin-resistant HeJ mice. These data indicate that a genetic mutation in HeJ mice that prevents LPS-induced synthesis of cytokines also renders HeJ mice refractory to the behavioral effects of LPS.