It is known that peripherally administered IL-1 and TNF alpha induce fever through mechanisms involving prostaglandin (PG)E-2. In this report, we compared the signaling cascade induced in the brain by TNF alpha and IL-1. Peripheral administration of TNF alpha-induced enhanced fever in IL-1 Receptor antagonist KO mice, suggesting that IL-1 is involved in the TNF alpha mediated fever. IL-1 alpha, but not TNFa, induced fever in IL-1 alpha/beta/TNF alpha KO mice, although central administration of TNF alpha-induced fever. Only IL-1 alpha, but not TNF alpha, induced IL-6 in the IL-1 alpha/beta/TNF alpha KO mouse brain, while both cytokines induced cyclooxygenase (Cox)-2. Icv administration of PGE(2) induced only transient fever in contrast to the TNF alpha- or IL-1 alpha-induced fever that lasted longer. Taken together, either IL-1 or TNF alpha induction in the brain is required for the response induced by TNF alpha but not by IL-1 alpha, and that both Cox-2 and IL-6 induction are required for prolonged febrile response against these cytokines. (C) 2007 Elsevier Inc. All rights reserved.