Interleukin-1 mediates endothelin-1-induced fever and prostaglandin production in the preoptic area of rats

Abstract

The intracerebroventricular 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 conducted in vivo and in vitro experiments in the rat to investigate 1) the hypothalamic region involved in ET-1-induced fever and PG biosynthesis and 2) whether hypothalamic IL-1 plays a role as a mediator of the above ET-1 activities. One hundred femtomoles 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 nanomoles of IL-1ra or 10 nM of a cell-permeable interleukin-1 converting enzyme inhibitor completely counteracted the effect of ET-1 on PGE2 release from the POA. One hundred nanomoles ET-1 also caused a significant increase in IL-1beta 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-1beta 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.

Febrile response induced by cecal ligation and puncture (CLP) in rats: involvement of prostaglandin E2 and cytokines

“…It is well known that the cytokines investigated in the present study, IL-1 , TNF-and IL-6, have the ability to induce the synthesis of COX-2, the key enzyme in the synthesis of prostaglandins from arachidonic acid in the CNS during the febrile response [3,24,[54][55][56][57][58]. In the present study, the peak of the febrile response (6 h) induced by CLP overlapped with an increase of IL-6 and PGE 2 in the hypothalamus, suggesting a direct relationship between centrally produced IL-6, PGE 2 and fever as previously suggested by other studies [59][60][61].…”

“…The entire hypothalamus was dissected from the brain using the following limits: the anterior border of the optic chiasm, the anterior border of the mammillary bodies, and the lateral hypothalamic sulci, with a depth of 2 mm. The total dissection time elapsed from decapitation was <2 min [24]. Each hypothalamus was divided into two equal parts, left and right sides on either side of the midline, and samples were randomized between left and right (for the determination of cytokines and PG levels), and immediately frozen to ¡70°C until analysis.…”

A crucial role for IL-6 in the CNS of rats during fever induced by the injection of live E. coli

“…Similarly, i.c.v administration of these antagonists also reduces the febrile response induced by i.c.v. injection of cytokines [38,[49][50][51].…”

“…Oxytetracycline hydrochloride (Terramicina ® ) was from PWzer (São Paulo, Brazil). The doses of all substances used in this study were chosen according to our previous studies [4,8,37,38] or were selected according to the results from preliminary dose-response studies in our laboratory.…”

Endocannabinoids, through opioids and prostaglandins, contribute to fever induced by key pyrogenic mediators

“…The doses of cannabinoid receptor antagonists and agonists, pyrogenic cytokines, prostaglandins, CRH and ET-1 used in this study are from previous studies from our lab (Fabricio et al, 2006;Fraga et al, 2009). The first set of experiments was designed to evaluate the effects of prior treatment (30 min before) with the CB1 receptor antagonist AM251 in the fever response induced by the pyrogenic cytokines IL-1β, TNF-α and IL-6.…”