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 core temperature on host defenses are poorly understood. Tumor necrosis factor alpha (TNF-α) is an early activator of host defenses and a major endogenous pyrogen. TNF-α expression is essential for survival in bacterial 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°C) to the febrile (39.5 to 40°C) range modifies systemic TNF-α expression in response to bacterial endotoxin (lipopolysaccharide). The early TNF-α secretion rate is enhanced, but the duration of maximal TNF-α production is shortened. We identified Kupffer cells as the predominant source of the excess TNF-α production in the warmer animals. The enhanced early TNF-α 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 indirect pathways. Therefore, expression of the endogenous pyrogen TNF-α is regulated by increments in core temperature during fever, generating an enhanced early, self-limited TNF-α pulse.