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.
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.
Department of Neuroscience, Osaka Bioscience Institute, Japan.
C
C
Cao
K
K
Matsumura
K
K
Yamagata
Y
Y
Watanabe
D000818:Animals; D001345:Autoradiography; D001831:Body Temperature / Q000187:drug effects; D002560:Cerebrovascular Circulation; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D005334:Fever / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008565:Membrane Proteins; D008578:Meninges / Q000098:blood supply*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011453:Prostaglandins / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D013462:Sulfur Radioisotopes; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*
D007375:Interleukin-1; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011453:Prostaglandins; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D013462:Sulfur Radioisotopes; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone