Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever

Abstract

We previously showed that intraperitoneal injection of lipopolysaccharide induced cyclooxygenase-2 (COX-2) mRNA in as yet unidentified cells of blood vessels and leptomeninges in the rat brain and proposed a possible role of these cells as the source of prostaglandin E2 in the genesis of fever (Cao et al., Brain Res., 697 (1995) 187-196). In the present study, to proceed further with this line of research, we addressed the following two questions: first, does a pyrogenic dose of interleukin-1 beta (IL-1 beta), an endogenous pyrogen, induce COX-2 mRNA in the brain blood vessels and leptomeninges? Secondly, if it does, what type of cells are positive for COX-2 mRNA? Intraperitoneal injection of recombinant human IL-1 beta (30 micrograms/kg) induced fever in rats and an in situ hybridization study revealed that faint but significant COX-2 mRNA signals appeared in the blood vessels and leptomeninges at 1.5 h after the injection (the early rising phase of fever). The mRNA signals increased in number and intensity at 4 h (early plateau phase), decreased at 6.5 h (early recovery phase), and completely disappeared by 10 h after the injection (late recovery phase). The COX-2 mRNA positive cells in the blood vessels were likely to be the endothelial cells since the corresponding cells in the adjacent mirror-imaged section also expressed mRNAs for intracellular adhesion molecule-1 and the type-I interleukin-1 receptor, although those in the leptomeninges still remained unidentified. These results imply that circulating IL-1 beta acts on its receptor on the endothelial cells of the brain vasculature to induce COX-2 mRNA, which is possibly responsible for the elevated level of PGE2 seen during fever.