EFFECT OF ACUTE SYSTEMIC INFLAMMATORY RESPONSE AND CYTOKINES ON THE TRANSCRIPTION OF THE GENES ENCODING CYCLOOXYGENASE ENZYMES (COX-1 AND COX-2) IN THE RAT-BRAIN

The aim of this study was to investigate the influence of the acute-ph ase response and the proinflammatory cytokines on the transcription of the genes encoding the limiting enzymes for the production of prostag landins, cyclooxygenase (COX)-1 and COX-2, in the rat brain. The bacte rial endotoxin lipopolysaccharide (intravenous and intraperitoneal) an d turpentine (intramuscular) were used as different models of inflamma tion in adult male rats, Animals were also killed at various times aft er intravenous administration of interleukin-1 beta, tumor necrosis fa ctor-alpha, and interleukin-6, and mRNAs encoding COX-I and COX-2 were assayed by in situ hybridization histochemistry. A profound transcrip tional activation of the gene encoding COX-2 was detected over blood v essels of the entire brain microvasculature, choroid plexus, and lepto meninges of lipopolysaccharide-challenged rats, Injection of the endot oxin intravenously also increased COX-2 gene expression within parvoce llular division of the hypothalamic paraventricular nucleus, It is int eresting that intramuscular turpentine injection stimulated transcript ion of COX-2 along endothelium of brain capillaries, and the signal of this transcript paralleled the inflammation of the left hind limb. A robust COX-2 mRNA signal was detected rapidly in the brain microvessel s of interleukin-l beta-injected rats, whereas tumor necrosis factor-a administration caused a modest but significant induction of this tran script, In contrast, intravenous injection of interleukin-6 did not al ter genetic expression of COX-2, and none of the above described model s affected the synthesis of COX-1 gene in the rat brain. These results indicate that specific cell populations, in particular vascular- and/ or perivascular-associated cells, are responsible for the central prod uction of prostaglandins during systemic inflammation, and circulating interleukin-1 beta is likely to be a potent mediator of this response .