RGD Reference Report - Granzyme-b is involved in mediating post-ischemic neuronal death during focal cerebral ischemia in rat model. - Rat Genome Database

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Granzyme-b is involved in mediating post-ischemic neuronal death during focal cerebral ischemia in rat model.

Authors: Chaitanya, GV  Schwaninger, M  Alexander, JS  Babu, PP 
Citation: Chaitanya GV, etal., Neuroscience. 2010 Feb 17;165(4):1203-16. Epub 2009 Nov 4.
RGD ID: 2325193
Pubmed: PMID:19895873   (View Abstract at PubMed)
DOI: DOI:10.1016/j.neuroscience.2009.10.067   (Journal Full-text)

Although peripheral immune cells infiltrate ischemic infarct tissue and elicit immune injury, the role of Cytotoxic T Lymphocytes (CTLs) and the toxins they release in mediating neuronal death is not well understood. Granzyme-b (Gra-b), a serine protease found in the cytoplasmic granules of CTLs and natural killer cells, plays an important role in inducing target cell death by activating several caspases and by initiating caspase-independent pathways that contribute to target cell death. To determine if CTLs and Gra-b are involved in post-ischemic cerebral cell death; we investigated the role of CD8(+) CTLs and Gra-b in ischemic rat brain infarct after transient middle cerebral artery occlusion (tMCAO) and in sham-operated animals. We observed that CTLs infiltrate the ischemic infarct within 1 h of reperfusion. There was a significant increase in Gra-b levels in the ischemic region starting from 1 h until 3 day which correlated with increased levels of chemokines (IP-10/CXCL10, IL-2) and TNF-alpha. Co-immunoprecipitation experiments show that Gra-b interacts with Bid, PARP, and caspase-3 in ischemic samples. Immunofluorescence analysis of Gra-b and TUNEL showed that Gra-b is present both in apoptotic and necrotic cells. Triple immunostaining further confirmed that the Gra-b positive degenerating cells were neurons. CTLs in close spatial proximity to degenerating neurons, increased levels of Gra-b, localization in neurons positive for TUNEL, and interaction with other pro-apoptotic proteins indicate that Gra-b and CTLs play a significant role in neuronal death following cerebral ischemia in the rat brain after tMCAO. Based on the above findings we support our hypothesis that Gra-b secreted from activated CTLs might be involved in aggravating post-ischemic damage by mediating neuronal death.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CXCL10Humanbrain infarction  ISOCxcl10 (Rattus norvegicus)protein:increased expression:brain (rat)RGD 
Cxcl10Ratbrain infarction  IEP protein:increased expression:brain (rat)RGD 
Cxcl10Mousebrain infarction  ISOCxcl10 (Rattus norvegicus)protein:increased expression:brain (rat)RGD 
GZMBHumanbrain infarction  ISOGzmb (Rattus norvegicus)protein:increased expression:brain (rat)RGD 
GzmbRatbrain infarction  IEP protein:increased expression:brain (rat)RGD 
GzmbMousebrain infarction  ISOGzmb (Rattus norvegicus)protein:increased expression:brain (rat)RGD 
IL2Humanbrain infarction  ISOIl2 (Rattus norvegicus)protein:increased expression:brain (rat)RGD 
Il2Ratbrain infarction  IEP protein:increased expression:brain (rat)RGD 
Il2Mousebrain infarction  ISOIl2 (Rattus norvegicus)protein:increased expression:brain (rat)RGD 
TNFHumanbrain infarction  ISOTnf (Rattus norvegicus)protein:increased expression:brain (rat)RGD 
TnfRatbrain infarction  IEP protein:increased expression:brain (rat)RGD 
TnfMousebrain infarction  ISOTnf (Rattus norvegicus)protein:increased expression:brain (rat)RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GzmbRatneuron apoptotic process  IDA  RGD 
GzmbRatpositive regulation of necroptotic process  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cxcl10  (C-X-C motif chemokine ligand 10)
Gzmb  (granzyme B)
Il2  (interleukin 2)
Tnf  (tumor necrosis factor)

Genes (Mus musculus)
Cxcl10  (C-X-C motif chemokine ligand 10)
Gzmb  (granzyme B)
Il2  (interleukin 2)
Tnf  (tumor necrosis factor)

Genes (Homo sapiens)
CXCL10  (C-X-C motif chemokine ligand 10)
GZMB  (granzyme B)
IL2  (interleukin 2)
TNF  (tumor necrosis factor)


Additional Information