Effects of the inhibition of cyclo-oxygenase 1 or 2 or 5-lipoxygenase on the activation of the hypothalamic-pituitary-adrenal axis induced by interleukin-1 beta in the male rat

The limited entry of interleukin-1 beta (IL-1 beta) into the central nervou s system has led to the hypothesis that IL-1 beta acts, through IL-1 beta r eceptors located notably on endothelial cells, on the release of prostaglan dins which in turn stimulate the hypothalamic-pituitary-adrenal (HPA) axis. We used cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2) and 5-lipo xygenase (5-LOX) inhibitors, before the injection of IL-1 beta, to explore the role of arachidonic acid metabolic pathways on HPA axis activation. Adu lt male rats were i.m injected 20 min before i.p injection of IL-1 beta, wi th (i): a COX-1/COX-2 inhibitor (ketoprofen); (ii) a COX-2 selective inhibi tor (NS 398); or (iii) a 5-LOX inhibitor (BW A4C). Following this, rats wer e killed 90 min after i.p. IL-1 beta injection and analysis for plasma adre nocorticotropic hormone (ACTH) and corticosterone concentrations and determ ination of anterior pituitary pro-opio melanocortin (POMC) gene transcripti on was conducted. Administration of the COX-1/COX-2 inhibitor led to a comp lete blockage of ACTH and corticosterone secretion and POMC gene transcript ion. The COX-2 inhibitor led to a complete blockade of ACTH secretion and P OMC gene transcription but had no effect on corticosterone secretion. The 5 -LOX inhibitor had no significant effect on any parameter. These results de monstrate the crucial role of eicosanoid pathways in mediating the stimulat ion of the HPA axis induced by IL-1 beta. Moreover, we found a clear dissoc iation of the effect of the blockage of COXs upon ACTH and corticosterone s ecretion, suggesting that IL-1 beta may act at the brain as well as at the adrenal cortex to stimulate the secretion of corticosterone.