Fever is a phylogenetically ancient response that is associated with improved survival in acute infections. In endothermic animals, fever is induced by a set of pyrogenic cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, and IL-6] that are also essential for survival in acute infections. We studied the influence of core temperature on cytokine expression using an anesthetized mouse model in which core temperature was adjusted by immersion in water baths. We showed that raising core temperature from basal (36.5-37.5 degrees C) to febrile (39.5-40 degrees C) levels increased peak plasma TNF-alpha and IL-6 levels by 4.1- and 2. 7-fold, respectively, and changed the kinetics of IL-1beta expression in response to lipopolysaccharide challenge. TNF-alpha levels were increased predominantly in liver, IL-1beta levels were higher in lung, and IL-6 levels were widely increased in multiple organs in the warmer mice. This demonstrates that the thermal component of fever may directly contribute to shaping the host response by regulating the timing, magnitude, and tissue distribution of cytokine generation during the acute-phase response.