Role of hypothalamic interleukin-1beta in fever induced by cecal ligation and puncture in rats

Bacterial endotoxin induces fever by causing the release of interleukin (IL)-1beta into the circulation or the brain. IL-1beta is believed to mediate fever via triggering the production and/or release of IL-6 in the hypothalamus. The present study examined whether IL-1beta and IL-6 in the hypothalamus of the rat are also involved in fever during bacterial sepsis caused by cecal ligation and puncture (CLP). CLP induces fever for 2 days. Polyclonal rabbit antibody against rat IL-1beta (anti-IL-1beta, 2 microg/microl) or control rabbit IgG (2 microg/microl) was unilaterally microinjected into the hypothalamus of rats immediately after or 24 h after CLP or sham-CLP surgery. Anti-IL-1beta injected 24 h after CLP (when fever was already present) or sham-CLP surgery did not affect fever. Microinjection of anti-IL-1beta into the hypothalamus immediately after surgery caused a significant decrease in body temperature during the night after CLP surgery and a 48% reduction of fever on the following day. Although blood plasma levels of IL-6 were significantly elevated 1.5, 6, 24, and 48 h after CLP surgery, there were no differences in IL-6 concentrations in the extracellular fluid of the anterior hypothalamus (collected by push-pull perfusion). These data suggest that fever due to bacterial sepsis is initiated by IL-1beta within the hypothalamus, and this febrile response, unlike endotoxin-induced fever, is not accompanied by elevation in the hypothalamic concentration of IL-6.