Febrile-range temperature modifies early systemic tumor necrosis factor alpha expression in mice challenged with bacterial endotoxin

Fever improves survival in acute infections, but the effects of increased c ore temperature on host defenses are poorly understood. Tumor necrosis fact or alpha (TNF-alpha) is an early activator of host defenses and a major end ogenous pyrogen, TNF-alpha expression is essential for survival in bacteria l infections but, if disregulated, can cause tissue injury, In this study, we show that passively increasing core temperature in mice from the basal ( 36.5 to 37.5 degrees C) to the febrile (39.5 to 40 degrees C) range modifie s systemic TNF-alpha expression in response to bacterial endotoxin (lipopol ysaccharide). The early TNF-alpha secretion rate is enhanced, but the durat ion of maximal TNF-alpha production is shortened. We identified Kupffer cel ls as the predominant source of the excess TNF-alpha production in the warm er animals. The enhanced early TNF-alpha production observed at the higher temperature in vivo could not be demonstrated in isolated Kupffer cells or in precision-cut liver slices in vitro, indicating the participation of ind irect pathways. Therefore, expression of the endogenous pyrogen TNF-alpha i s regulated by increments in core temperature during fever, generating an e nhanced early, self-limited TNF-alpha. pulse.