Interleukin (IL)-6 is an important mediator of the host response to disease and has been proposed, largely based upon circumstantial evidence, as the principal endogenous circulating pyrogen responsible for activating CNS mechanisms in fever during infection and inflammation. In the present investigation, we studied the role of peripheral IL-6 in fever and its relationship with IL-1, itself an important endogenous pyrogen and a potent stimulus of IL-6 production. Injection of lipopolysaccharide (LPS) into a sterile, subcutaneous air pouch (i.po.) in rats evoked an increase in body temperature which peaked at 3 h, and which was abolished in animals pretreated (intraperitoneally) with IL-6 antiserum. The increase in body temperature was accompanied by a significant elevation in concentrations of (immunoreactive) IL-1 and IL-6 at the site of inflammation (pouch), but only IL-6 in the circulation and cerebrospinal fluids. We propose that much of the circulating IL-6 originates at the site of inflammation, since injection of human recombinant (hr)IL-6 (i.po.) was detected (10 min after the injection) in the plasma using an ELISA specific for human IL-6. However, despite the relatively high concentration of IL-6 injected (25 microg kg-1, i.po.), this cytokine had no effect on body temperature when injected alone, but did induce fever when co-injected with a non-pyrogenic dose (when given alone) of IL-1beta, and exacerbated the fever to a pyrogenic dose of IL-1beta. The results from the present study demonstrate that IL-6 is a circulating endogenous pyrogen during LPS-induced fever, which acts in concert with IL-1beta at the local site of inflammation, before entering the circulation. Circulating IL-6 can then activate CNS mechanisms resulting in the development of the febrile response during disease.