RGD Reference Report - Anti-inflammatory effects of the 70 kDa heat shock protein in experimental stroke. - Rat Genome Database

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

Authors: Zheng, Z  Kim, JY  Ma, H  Lee, JE  Yenari, MA 
Citation: Zheng Z, etal., J Cereb Blood Flow Metab. 2008 Jan;28(1):53-63. Epub 2007 May 2.
RGD ID: 5688754
Pubmed: PMID:17473852   (View Abstract at PubMed)
DOI: DOI:10.1038/sj.jcbfm.9600502   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
middle cerebral artery infarction  ISOHspa4 (Rattus norvegicus)5688754; 5688754rat gene in mouse modelRGD 
middle cerebral artery infarction  IMP 5688754rat gene in mouse modelRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Hspa4  (heat shock protein family A (Hsp70) member 4)

Genes (Mus musculus)
Hspa4  (heat shock protein 4)

Genes (Homo sapiens)
HSPA4  (heat shock protein family A (Hsp70) member 4)


Additional Information