Pyrogenic cytokines injected into the rat cerebral ventricle induce cyclooxygenase-2 in brain endothelial cells and also upregulate their receptors

Peripheral immunological insults induce interleukin (IL)-1 beta and IL-6 in the brain. To elucidate the mechanism(s) of fever evoked by these brain-de rived cytokines, and possible interactions between them, we examined in rat s: (i) whether cyclooxygenase-2 is responsible for fever evoked by central injection of these cytokines; (ii) if so, where in the brain cyclooxygenase -2 is induced; (iii) where the receptors for these cytokines are located; a nd (iv) how the expression of these receptors is influenced by the cytokine s. Intracerebroventricular injection of these cytokines evoked fever that w as suppressed by a cyclooxygenase-2 inhibitor. Brain endothelium was the si te of cyclooxygenase-2 induction by these cytokines. IL-1 receptor (IL-1R) was constitutively expressed in brain endothelium, and its mRNA was further upregulated by either cytokine. IL-6R mRNA was constitutively expressed in the cerebral cortex, and was newly induced in as yet unidentified cells in brain blood vessels by either cytokine. Messenger RNAs for cyclooxygenase- 2, IL-1R, and IL-6R were often observed in the same blood vessels. These re sults suggest that COX-2 induced in brain endothelium is, at least in part, involved in the fever evoked by these cytokines, and that one possible int eraction between these two cytokines is mutual upregulation of their recept ors in the endothelium or perivascular cells, resulting in augmentation of their actions.