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

Sundgren-Andersson, Anna K., Pernilla Östlund, and Tamas Bartfai. IL-6 is essential in TNF-a-induced fever. Am. J. Physiol. 275 (Regulatory Integrative Comp. Physiol. 44): R2028–R2034, 1998.—Tumor necrosis factor-a (TNF-a) is a pleiotropic cytokine that orchestrates an array of local and systemic effects. For instance, acute exposure to a high dose of TNF-a results in septic shock and fever. We have used interleukin-1b (IL-1b)and interleukin-6 (IL-6)-deficient mice, along with their wild-type equivalents, to define a role for TNF-a in fever. Briefly, the mice produced prostaglandin E2-dependent fevers in response to recombinant murine TNF-a (rmTNF-a). Furthermore, rmTNF-a (12 μg/mouse ip) triggered a febrile response in IL-1b-deficient mice as well as in their corresponding wild-type controls. In contrast, the IL-6-deficient mice were resistant to rmTNF-a (4.5 μg/mouse ip), although their wild-type counterparts readily mounted a fever. In the IL-6-deficient mice, moreover, the febrile response to rmTNF-a could be restored by a central administration of rat recombinant IL-6 (500 ng/mouse icv). We thus conclude that TNF-a can trigger fever independent of IL-1b 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-a-induced fever.