The heat shock response inhibits NF-kappaB activation, nitric oxide synthase type 2 expression, and macrophage/microglial activation in brain.
The heat shock response (HSR) provides protection against stress-induced damage, and also prevents initiation of inflammatory gene expression via inhibition of NFkappaB activation. This article describes experiments demonstrating that the HSR prevents induction of nitric oxide synthase type 2 (NOS2) in rat brain. Twenty four hours after intrastriatal injection of lipopolysaccharide (LPS), IL-1beta, and IFN-gamma, NOS2 immunoreactive cells were detected in striatum, corpus callosum, and to a lesser extent in cortex. Induction 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-positive staining cells to background levels. Staining for EDI antigen revealed that the HSR also suppressed microglial/brain macrophage activation in the same areas. Striatal injection of LPS and cytokines induced the rapid activation of NFkappaB, and this activation was prevented by prior HS, which also increased brain IkappaB-alpha expression. These results suggest that establishment of a HSR can reduce inflammatory gene expression in brain, mediated by inhibition of NFkappaB activation, and may therefore offer a novel approach to treatment and prevention of neurological disease and trauma.
Heneka
M T
MT
Department of Neurology, University of Bonn, Germany.
Sharp
A
A
Klockgether
T
T
Gavrilyuk
V
V
Feinstein
D L
DL
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D005260:Female; D018869:Heat-Shock Response / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley
D016328:NF-kappa B; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat