The role of tumor necrosis factor (TNF) in the febrile and metabolic responses of rats to intraperitoneal injection of a high dose of lipopolysaccharide

Injection of a high dose of lipopolysaccharide (LPS) induces a septic-shock -like state, which can be accompanied by phases of hypothermia and phases o f fever. In the present study we monitored body core temperature and locomo tor activity, both by remote radiotelemetry, as well as changes in food int ake, body mass and water intake for 3 days after an intraperitoneal (i.p.) injection of a high dose of LPS (5 mg/kg) along with sterile 0.9% saline or a neutralizing form of the soluble tumor necrosis factor (TNF) type 1 rece ptor (referred to as TNF-binding protein, TNF bp). Intraperitoneal injectio n of LPS rapidly induced high concentrations of TNF in the plasma and perit oneal lavage fluid. TNF was undetectable in the plasma and peritoneal lavag e fluid of animals co-injected with LPS and TNF: bp implying neutralization of peripheral bioactive TNF Administration of LPS induced hypothermia by a bout 1.5 degreesC, which lasted fur 5 h after injection. During the light-t ime periods of days 2 and 3 after injection, the rats developed a robust fe ver. Treatment with TNF bp resulted in a faster recovery from the LPS-induc ed hypothermia so that the rats developed a pronounced fever on the day of injection. Locomotor activity during night-time periods was suppressed in L PS-treated animals. The LPS-induced depression of night-time activity was n ot antagonized by co-injection of TNF bp. On day 1 after the injection of L PS, food intake reduced to virtually zero, water intake fell to about 30% o f the control value and body mass dropped by 25 g (about 10% of total body mass). With the exception of body mass, these variables recovered slowly du ring days 2 and 3 after LPS injection, but did not reach the control values . The LPS-induced decreases in food intake, body mass and water intake were significantly attenuated by the treatment with TNF bp. These results confi rm that TNF contributes significantly to the rats' responses to intraperito neal injection of a high dose of LPS. The fact that treatment with TNF bp a ccelerated and improved the rats' ability to develop a febrile response sup ports the view that the fever is beneficial, since all other metabolic resp onses measured in this study were normalized more effectively in those rats that developed a faster and more pronounced increase in body temperature.