The intracerebroventricular (i.c.v.) injection of endothelin-1 (ET-1) induces fever and increases PG levels in the cerebrospinal fluid of rats. Likewise, the injection of IL-1 into the preoptic area (POA) of the rat hypothalamus causes both fever and increased PG production. In this study we counducted in vivo and in vitro experiments in the rat to investigate: i) the hypothalamic region involved in ET-1-induced fever and PG biosynthesis; ii) whether hypothalamic IL-1 plays a role as a mediator of the above ET-1 activities. One hundred fmol of ET-1 increased body temperature when injected in the POA of conscious Wistar rats; this effect was significantly counteracted by the coinjection of 600 pmol IL-1 receptor antagonist (IL-1ra). In experiments on rat hypothalamic explants, 100 nM ET-1 caused a significant increase in PGE₂ production and release from the whole hypothalamus and from the isolated POA, but not from the retrochiasmatic region, in 1-h incubations. Six nM of IL-1ra or 10 nM of a cell-permeable interleukin-1 converting enzyme (ICE) inhibitor completely counteracted the effect of ET-1 on PGE₂ release from the POA. One hundred nM ET-1 also caused a significant increase in IL-1 immunoreactivity released into the bath solution of hypothalamic explants after 1 h of incubation, although during such time ET-1 failed to modify the gene expression of IL-1 and other pyrogenic cytokines within the hypothalamus. In conclusion, our results show that ET-1 increases IL-1 production in the POA, and this effect appears to be correlated to ET-1-induced fever in vivo, as well as to PG production in vitro.