RGD Reference Report - TACE/ADAM17-TNF-alpha pathway in rat cortical cultures after exposure to oxygen-glucose deprivation or glutamate. - Rat Genome Database

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TACE/ADAM17-TNF-alpha pathway in rat cortical cultures after exposure to oxygen-glucose deprivation or glutamate.

Authors: Hurtado, O  Lizasoain, I  Fernandez-Tome, P  Alvarez-Barrientos, A  Leza, JC  Lorenzo, P  Moro, MA 
Citation: Hurtado O, etal., J Cereb Blood Flow Metab 2002 May;22(5):576-85.
RGD ID: 632021
Pubmed: PMID:11973430   (View Abstract at PubMed)
DOI: DOI:10.1097/00004647-200205000-00009   (Journal Full-text)

The role of the tumor necrosis factor (TNF)-alpha convertase (TACE/ADAM17) in the adult nervous system remains poorly understood. The authors have previously demonstrated that TACE is upregulated in rat forebrain slices exposed to oxygen-glucose deprivation (OGD). They have now used rat mixed cortical cultures exposed to OGD or glutamate to study (1) TACE expression and localization, and (2) the effects of TNF-alpha release on cell viability. OGD-or glutamate-caused TNF-alpha release, an effect that was blocked by the TACE inhibitor BB3103 (BB) (0.1-1 micromol/L; control: 1.67 +/- 0.59; OGD: 6.59 +/- 1.52; glutamate: 3.38 +/- 0.66; OGD +/- BB0.1: 3.23 +/- 0.67; OGD +/- BB1: 1.33 +/- 0.22 pg/mL, n = 6, P < 0.05). Assay of TACE activity as well as Western blot showed that TACE expression is increased in OGD-or glutamate-exposed cells. In control cultures, TACE immunoreactivity was present in some microglial cells, whereas, after OGD or glutamate, TACE immunostaining appeared in most microglial cells and in some astrocytes. Conversely, BB3103 (0.1 micromol/L) caused apoptosis after glutamate exposure as shown by annexin and Hoechst 33342 staining and caspase-3 activity, an effect mimicked by the proteasome inhibitor MG-132 (caspase activity: glutamate: 5.1 +/- 0.1; glutamate + BB: 7.8 +/- 0.8; glutamate + MG: 11.9 +/- 0.5 pmol. min(-1) mg(-1) protein, n = 4, P < 0.05), suggesting that translocation of the transcription factor NF-kappaB mediates TNF-alpha-induced antiapoptotic effect. Taken together, these data demonstrate that, in rat mixed neuronal-glial cortical cultures exposed to OGD or glutamate, (1) TACE/ADAM17 activity accounts for the majority of TNF-alpha shedding, (2) an increase in glial TACE expression contributes to the rise in TNF-alpha, and (3) TNF-alpha release in this setting inhibits apoptosis via activation of the transcription factor NF-kappaB.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of apoptotic process  IDA 632021 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Adam17  (ADAM metallopeptidase domain 17)

Objects referenced in this article
Gene Tnf tumor necrosis factor Rattus norvegicus

Additional Information