Influence of hypothermia on post-ischemic inflammation: role of nuclear factor kappa B (NFkappaB).
Mild hypothermia is one of the most robust neuroprotectant studied in the laboratory to date. The reasons for this protective effect are likely multifactorial, but work from our laboratory and others have shown that this protection is associated with remarkable suppression of the inflammatory response that accompanies brain ischemia. Consistently, laboratories have shown that small decreases in brain temperature to 30-34 degrees C result in reduced inflammatory cell infiltrate, less microglial activation, and reduction of a variety of inflammatory mediators such as nitric oxide, inflammatory cytokines and superoxide. Nuclear factor-kappaB (NFkappaB) is a transcription factor that is activated after cerebral ischemia. NFkappaB activation leads to the expression of many inflammatory genes involved in the pathogenesis of stroke. Our laboratory has shown that hypothermia decreases NFkappaB translocation and binding activity, by affecting NFkappaB regulatory proteins. Mild hypothermia appears to suppress phosphorylation of NFkappaB's inhibitory protein (IkappaB-alpha) by decreasing expression and activity of IkappaB kinase-gamma (IKK). As a consequence, hypothermia suppressed gene expression of two NFkappaB target genes, inducible nitric oxide synthase and TNF-alpha. These data suggest that the protective effect of hypothermia on cerebral injury is, in part, related to NFkappaB inhibition due to decreased activity of IKK.
Yenari
Midori A
MA
Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121, United States. yenari@alum.mit.edu
Han
Hyung Soo
HS
D000818:Animals; D001831:Body Temperature / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology*; D019610:Cytoprotection / Q000502:physiology*; D004660:Encephalitis / Q000503:physiopathology / Q000517:prevention & control* / Q000628:therapy*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D007036:Hypothermia, Induced; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*
D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B