The heat shock response inhibits NF-kappa B activation, nitric oxide synthase type 2 expression, and macrophage/microglial activation in brain

The heat shock response (HSR) provides protection against stress-induced da mage, and also prevents initiation of inflammatory gene expression via inhi bition of NF kappa B activation. This article describes experiments demonst rating that the HSR prevents induction of nitric oxide synthase type 2 (NOS 2) in rat brain. Twenty four hours after intrastriatal injection of lipopol ysaccharide (LPS), IL-I beta, and IFN-gamma, NOS2 immunoreactive cells were detected in striatum, corpus callosum and to a lesser extent in cortex. In duction of a HSR by whole body warming to 41 degrees C for 20 minutes, done 1 day before LPS plus cytokine injection, reduced the number of NOS2-posit ive staining cells to background levels. Staining for ED1. antigen revealed that the HSR also suppressed microglial / brain macrophage activation in t he same areas. Striatal injection of LPS and cytokines induced the rapid ac tivation of NF kappa B, and this activation was prevented by prior HS, whic h also increased brain I kappa B-alpha. expression. These results suggest t hat establishment of a HSR can reduce inflammatory gene expression in brain , mediated by inhibition of NF kappa B activation, and may therefore offer a novel approach to treatment and prevention of neurological disease and tr auma.