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Anti-inflammatory effects of the 70 kDa heat shock protein in experimental stroke.

Authors
 Zhen Zheng  ;  Jong Youl Kim  ;  Hualong Ma  ;  Jong Eun Lee  ;  Midori A Yenari 
Citation
 JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, Vol.28(1) : 53-63, 2008 
Journal Title
 JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 
ISSN
 0271-678X 
Issue Date
2008
MeSH
Analgesics/immunology ; Analgesics/metabolism* ; Animals ; Astrocytes/immunology ; Astrocytes/metabolism ; Astrocytes/pathology ; Cell Death/genetics ; Cell Death/immunology ; Coculture Techniques ; Disease Models, Animal ; HSP70 Heat-Shock Proteins/biosynthesis* ; HSP70 Heat-Shock Proteins/genetics ; HSP70 Heat-Shock Proteins/immunology ; I-kappa B Kinase/genetics ; I-kappa B Kinase/immunology ; I-kappa B Kinase/metabolism ; Infarction, Middle Cerebral Artery/genetics ; Infarction, Middle Cerebral Artery/immunology ; Infarction, Middle Cerebral Artery/metabolism* ; Infarction, Middle Cerebral Artery/pathology ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/pathology ; Macrophage Activation/genetics ; Macrophage Activation/immunology ; Macrophages/immunology ; Macrophages/metabolism ; Macrophages/pathology ; Mice ; Mice, Transgenic ; Microglia/immunology ; Microglia/metabolism ; Microglia/pathology ; Multiprotein Complexes/genetics ; Multiprotein Complexes/immunology ; Multiprotein Complexes/metabolism ; NF-kappa B/genetics ; NF-kappa B/immunology ; NF-kappa B/metabolism ; Phosphorylation ; Rats
Keywords
heat shock proteins ; inflammation ; ischemia ; microglia ; neuroprotection ; nuclear factor-kappa B
Abstract
The 70-kDa heat shock protein (Hsp70) is involved in protecting the brain from a variety of insults including stroke. Although the mechanism has been largely considered to be because of its chaperone functions, recent work indicates that Hsp70 also modulates inflammatory responses. To explore how and whether Hsp70 regulate immune responses in brain ischemia, mice overexpressing Hsp70 (Hsp Tg) were subjected to 2 h middle cerebral artery occlusion, followed by 24 h reperfusion. Parallel experiments were performed using a brain inflammation model. Hsp Tg microglia cocultured with astrocytes were used to evaluate the direct effects of Hsp70 on cytotoxicity of microglia. Compared with wild-type (Wt) littermates, Hsp Tg mice showed decreased infarct size and improved neurological deficits. The number of activated microglia/macrophages were also reduced in ischemic brains of Hsp Tg mice. Similar observations were made in a model of brain inflammation that does not result in brain cell death. Overexpression of Hsp70 in microglia completely prevented microglia-induced cytotoxicity to astrocytes. Activation of the inflammatory transcription factor, nuclear factor-kappaB (NF-kappaB) was inhibited significantly in Hsp Tg mice and microglia. This was associated with decreased phosphorylation of NF-kappaB inhibitor protein, IkappaBalpha, and decreased expression of several NFkappaB-regulated genes. Co-immunoprecipitation studies revealed an interaction of Hsp70 with NF-kappaB and IkappaBalpha, but not with IkappaB kinase, IKKgamma, suggesting that Hsp70 binds to the NF-kappaB:IkappaB complex preventing IkappaB phosphorylation by IKK. The findings of the present work establish an anti-inflammatory role for Hsp70 in the context of brain ischemia as a novel mechanism of protection.
Full Text
http://www.nature.com/jcbfm/journal/v28/n1/full/9600502a.html
DOI
10.1038/sj.jcbfm.9600502
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jong Youl(김종열) ORCID logo https://orcid.org/0000-0002-8340-2894
Lee, Jong Eun(이종은) ORCID logo https://orcid.org/0000-0001-6203-7413
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/107675
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