Several peptides (cytokines), viz., interleukin-1 (IL-1), interferon-alpha (IFN-alpha), interleukin-6 (IL-6), tumor necrosis factor (TNF), are formed in response to conditions causing tissue inflammation or damage and are implicated in reactive changes of the host, including fever, while IL-1 has been considered an important mediator of fever, the other cytokines, specifically IL-6 and TNF, have recently acquired prominence. The present study extends earlier research on IL-1 and addresses the question of the role of IL-6 and TNF in the genesis of fever. Experiments were conducted in the conscious cat, and IL-6 and TNF were assayed concomitantly in cerebrospinal fluid (CSF) from the third ventricle using specific bioassays. In the absence of fever, IL-6 was usually below the threshold of the assay (4-32 pg/ml), while TNF appeared measurable (424 +/- 57 pg/ml) in most experiments. A single intravenous injection of endotoxin (bolus) or continuous infusion of IL-1 at doses eliciting a sustained fever increased CSF levels of IL-6, but had no effect on concentrations of TNF. Intracerebroventricular injection of a pyrogenic dose of endotoxin led to an elevation of TNF and IL-6 and, in either case, the effect was manifest during the latent period before the fever. In addition, by the same route, IL-1 caused a rise in IL-6. We conclude that brain is intrinsically capable of producing both IL-6 and TNF depending on the site of challenge. However, since IL-6 CSF levels are elevated regardless of the site of pyrogen injection, IL-6 lends itself better to a role in the pathogenesis of fever.