INTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR IN CEREBROSPINAL-FLUID - CHANGES DURING PYROGEN FEVER

Several peptides (cytokines), viz., interleukin-1 (IL-1), interferon-a lpha (IFN-alpha), interleukin-6 (IL-6), tumor necrosis factor (TNF), a re formed in response to conditions causing tissue inflammation or dam age and are implicated in reactive changes of the host, including feve r. while IL-1 has been considered an important mediator of fever, the other cytokines, specifically IL-6 and TNF, have recently acquired pro minence. The present study extends earlier research on IL-1 and addres ses 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 ven tricle using specific bioassays. In the absence of fever, IL-6 was usu ally below the threshold of the assay (4-32 pg/ml), while TNF appeared measurable (424 +/- 57 pg/ml) in most experiments. A single intraveno us injection of endotoxin (bolus) or continuous infusion of IL-1 at do ses 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 a nd, in either case, the effect was manifest during the latent period b efore 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 bo th 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.