IL-6 is essential in TNF-α-induced fever

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine that orchestrates an array of local and systemic effects. For instance, acute exposure to a high dose of TNF-alpha results in septic shock and fever. We have used interleukin-1 beta (IL-1 beta)- and interleukin-6 (IL-6)-deficient mice, along with their wild-type equivalents, to define a role for TNF-alpha in fever. Briefly, the mice produced prostaglandin En-dependent fevers in response to recombinant murine TNF-alpha (rmTNF-alpha). Furthermore, rmTNF-alpha (12 mu g/mouse ip) triggered a febrile response in IL-1 beta-deficient mice as well as in their corresponding wild-type controls. In contrast, the IL-6-deficient mice were resistant to rmTNF-alpha (4.5 mu g/mouse ip), although their wild-type counterparts readily mounted a fever. In the IL-6-deficient mice, moreover, the febrile response to rmTNF-alpha could be restored by a central administration of rat recombinant IL-6 (500 ng/mouse icy). We thus conclude that TNF-alpha can trigger fever independent of IL-1 beta but dependent on IL-6. We also suggest that central, rather than peripheral, IL-6 (plasma IL-6 was measured 2 h after pyrogenic challenge) is essential in TNF-alpha-induced fever.