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‐1β in the Male Rat

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Abstract
The limited entry of interleukin-1β (IL-1β) into the central nervous system has led to the hypothesis that IL-1β acts, through IL-1β receptors located notably on endothelial cells, on the release of prostaglandins 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-lipoxygenase (5-LOX) inhibitors, before the injection of IL-1β, to explore the role of arachidonic acid metabolic pathways on HPA axis activation. Adult male rats were i.m injected 20 min before i.p injection of IL-1β, with (i): a COX-1/COX-2 inhibitor (ketoprofen); (ii) a COX-2 selective inhibitor (NS 398); or (iii) a 5-LOX inhibitor (BW A4C). Following this, rats were killed 90 min after i.p. IL-1β injection and analysis for plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations and determination of anterior pituitary pro-opio melanocortin (POMC) gene transcription was conducted. Administration of the COX-1/COX-2 inhibitor led to a complete blockage of ACTH and corticosterone secretion and POMC gene transcription. The COX-2 inhibitor led to a complete blockade of ACTH secretion and POMC gene transcription but had no effect on corticosterone secretion. The 5-LOX inhibitor had no significant effect on any parameter. These results demonstrate the crucial role of eicosanoid pathways in mediating the stimulation of the HPA axis induced by IL-1β. Moreover, we found a clear dissociation of the effect of the blockage of COXs upon ACTH and corticosterone secretion, suggesting that IL-1β may act at the brain as well as at the adrenal cortex to stimulate the secretion of corticosterone.

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