Induction of pro-inflammatory cytokine mRNAs in the brain after peripheralinjection of subseptic doses of lipopolysaccharide in the rat

Although it is generally accepted that pro-inflammatory cytokines produced by cells of the central nervous system play important roles in the communic ation between the central nervous system and the immune system during sepsi s, it is not clear whether these cytokines are produced in the brain under subseptic conditions. In this study, we used in situ hybridization to exami ne the mRNA expression of the pro-inflammatory cytokines IL-1 beta and TNF alpha in the brains of rats 2 and 12 h after they were challenged by periph eral injections of lipopolysaccharide (LPS) ranging from 0.01 to 1000 mu g/ kg. Unlike septic doses of LPS (> 500 mu g/kg), which induce global express ion of pro-inflammatory cytokines in the brain, subseptic doses of LPS (0.0 1-10 mu g/kg) induced IL-1 beta and TNF alpha mRNA expression only in the c horoid plexus, the circumventricular organs, and meninges. The expression o f the cytokine-responsive immediate early gene I kappa B alpha was induced in the brain after doses of LPS as low as 0.1 mu g/kg. I kappa B alpha mRNA expression was confined to sites where rt-rp and TNF alpha were expressed. These results indicate that the induction and action of pro-inflammatory c ytokines during subseptic infection occur at the blood-brain barrier and at circumventricular organs, which may be sites for elaboration of signal mol ecules that communicate peripheral immune status to the brain. Published by Elsevier Science B.V.