Cytokines and fever. Mechanisms and sites of action.

The cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha induce increases in body temperature via direct and indirect actions on the brain and are believed to act as endogenous pyrogens. We studied the mechanisms of action of these cytokines on fever in rats. Local administration of lipopolysaccharide (LPS) into a subcutaneous air pouch elicits marked fever, accompanied by increases in the levels of TNF-alpha, IL-1, and IL-6 in the pouch, but only IL-6 in the plasma. Thus, TNF-alpha and IL-1 probably act locally to stimulate the release of a secondary circulating mediator(s) (e.g., IL-6) that can interact with the brain. Neural afferents have also been implicated in relaying messages to the brain. Pyrogenic responses are reportedly attenuated by subdi-aphragmatic vagotomy; however, we failed to observe inhibition of fever in vagotomized rats injected with either LPS or a pyrogenic dose of IL-1, although behavioral responses are abolished.