We investigated the role and interaction between tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6 in the development of fever and their involvement in brain and systemic pathways in response to localized tissue inflammation caused by injection of turpentine (TPS) in the rat. Intramuscular injection of 10 microl TPS caused significant increases in body temperature, of up to 2 degrees C, compared with saline-treated animals. Fevers were maximal 7-8 h after injection and were preceded by significant increases in plasma bioactive IL-6. No changes in circulating bioactive IL-1 or TNF-alpha were detected. Systemic injection of IL-1 receptor antagonist (IL-1ra, 2 mg/kg i.p.) or anti-TNF-alpha antiserum (0.4 ml i.v.) almost completely abolished the febrile responses to TPS over 8 h and markedly inhibited the rise in plasma IL-6 bioactivity measured 6 h after TPS. To test the involvement of brain cytokines, anti-TNF-alpha antiserum and IL-1ra were injected intracerebroventricularly. Injections of anti-TNF-alpha antiserum (3 microl/rat i.c.v.) or IL-1ra (400 microg/kg i.c.v.) significantly (P < 0.01 and P < 0.05, respectively) inhibited fever induced by TPS. These data suggest that both localized peripheral and brain IL-1 and TNF-alpha are involved directly in the pyrogenic response to inflammation. The results indicate that, in the periphery, IL-1 and TNF-alpha cause increased production of IL-6, the most likely candidate as a circulating endogenous pyrogen.