FEBRILE RESPONSE TO TISSUE INFLAMMATION INVOLVES BOTH PERIPHERAL AND BRAIN IL-1 AND TNF-ALPHA IN THE RAT

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 l ocalized tissue inflammation caused by injection of turpentine (TPS) i n the rat. Intramuscular injection of 10 mu l TPS caused significant i ncreases in body temperature, of up to 2 degrees C, compared with sali ne-treated animals. Fevers were maximal 7-8 h after injection and were preceded by significant increases in plasma bioactive IL-6. No change s in circulating bioactive IL-1 or TNF-alpha were detected. Systemic i njection of IL-1 receptor antagonist (IL-1ra, 2 mg/kg ip) or anti-TNF- alpha antiserum (0.4 ml iv) almost completely abolished the febrile re sponses 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 intracere broventricularly. Injections of anti-TNF-alpha antiserum (3 mu l/rat i cv) or IL-1ra (400 mu g/kg icv) 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 di rectly 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 pyroge n.