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The Journal of Neuroscience, December 15, 1999, 19(24):10923-10930

An Essential Role of Interleukin-1beta in Mediating NF-kappa B Activity and COX-2 Transcription in Cells of the Blood-Brain Barrier in Response to a Systemic and Localized Inflammation But Not During Endotoxemia

Nathalie Laflamme, Steve Lacroix, and Serge Rivest

Laboratory of Molecular Endocrinology, Centre de Recherche de l'Université Laval Research Center and Department of Anatomy and Physiology, Laval University, Québec, Canada G1V 4G2

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-kappa B) 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 kappa Balpha (Ikappa Balpha , index of NF-kappa B 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 Ikappa Balpha 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 Ikappa Balpha 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-kappa B molecules and PGs within endothelial cells of the BBB in an experimental model of intramuscularly turpentine-induced inflammation but not during endotoxemia.

Key words: blood vessels; circumventricular organs; endothelial cells; in situ hybridization histochemistry; inflammation; interleukin-1beta -deficient mice; immunocytochemistry; lipopolysaccharide; proinflammatory cytokines; microglia; macrophages; septic shock; transcription factor


Copyright © 1999 Society for Neuroscience  0270-6474/99/192410923-08$05.00/0


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