title: An essential role of interleukin-1beta in mediating NF-kappaB activity and COX-2 transcription in cells of the blood-brain barrier in response to a systemic and localized inflammation but not during endotoxemia.
abstract: When released into the bloodstream, proinflammatory cytokines have the ability to trigger the transcription of different genes in cells of the blood-brain barrier (BBB), including members of the nuclear factor kappa B (NF-kappaB) family and cyclooxygenase-2 (COX-2), the limiting enzyme for the formation of prostaglandins (PGs). The present study investigated the possibility that interleukin-1beta (IL-1beta) plays an essential role in these events during a systemic inflammatory response. Both wild-type and IL-1beta-deficient mice were killed at different times after two different immunogenic stimuli, i.e., intraperitoneal lipopolysaccharide (LPS) injection and intramuscular turpentine injection, used here as a model of systemic localized inflammatory insult. The inhibitory factor kappaBalpha (IkappaBalpha, index of NF-kappaB activity) and COX-2 transcripts were detected throughout the brain by means of in situ hybridization. Systemic LPS injection caused a strong and rapid expression of IkappaBalpha in endothelial cells lining the BBB of large and small blood vessels and thereafter within parenchymal microglia across the brain. This treatment also provoked a transient expression of COX-2 along cells of the vascular system, and the expression pattern and intensity of the signal for both transcripts were essentially the same in wild-type and IL-1beta-deficient animals. In contrast, the induction of these genes that was quite selective to the cells of the BBB in response to intramuscularly turpentine insult was completely abolished in IL-1beta-deficient mice. Indeed, a late and prolonged expression of IkappaBalpha and COX-2 mRNAs was found along the cerebral blood vessels in response to the sterile and localized inflammation in wild-type mice, whereas such induction was absent in the brain of IL-1beta-deficient animals. These results indicate that IL-1beta has an obligatory role in the activation of NF-kappaB molecules and PGs within endothelial cells of the BBB in an experimental model of intramuscularly turpentine-induced inflammation but not during endotoxemia.
authors.affiliation: Laboratory of Molecular Endocrinology, Centre de Recherche de l'Université Laval Research Center, Department of Anatomy, Laval University, Québec, Canada G1V 4G2.
authors.forename: N
authors.initials: N
authors.lastname: Laflamme
authors.forename: S
authors.initials: S
authors.lastname: Lacroix
authors.forename: S
authors.initials: S
authors.lastname: Rivest
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D051546:Cyclooxygenase 2; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D019446:Endotoxemia / Q000235:genetics / Q000503:physiopathology*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000235:genetics / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D014158:Transcription, Genetic / Q000502:physiology*; D014425:Turpentine / Q000494:pharmacology
chemical_list: D020672:I-kappa B Proteins; D007375:Interleukin-1; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D014425:Turpentine