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Titolo:
Up-regulation of TNF-alpha convertase (TACE/ADAM17) after oxygen-glucose deprivation in rat forebrain slices
Autore:
Hurtado, O; Cardenas, A; Lizasoain, I; Bosca, L; Leza, JC; Lorenzo, P; Moro, MA;
Indirizzi:
Univ Complutense Madrid, Fac Med, Dept Farmacol, E-28040 Madrid, Spain Univ Complutense Madrid Madrid Spain E-28040 acol, E-28040 Madrid, Spain Univ Complutense Madrid, Fac Farm, Inst Bioquim, CSIC, E-28040 Madrid, Spain Univ Complutense Madrid Madrid Spain E-28040 CSIC, E-28040 Madrid, Spain
Titolo Testata:
NEUROPHARMACOLOGY
fascicolo: 8, volume: 40, anno: 2001,
pagine: 1094 - 1102
SICI:
0028-3908(200106)40:8<1094:UOTC(A>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
NECROSIS-FACTOR-ALPHA; NITRIC-OXIDE SYNTHASE; AMYLOID PRECURSOR PROTEIN; SECRETASE CLEAVAGE; PROCESSING ENZYME; DOWN-REGULATION; GLIAL-CELLS; CYCLIC-GMP; EXPRESSION; METALLOPROTEASE;
Keywords:
disintegrin; metalloproteinase; ischemia; cytokines; nitric oxide; stroke;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
48
Recensione:
Indirizzi per estratti:
Indirizzo: Moro, MA Univ Complutense Madrid, Fac Med, Dept Farmacol, E-28040 Madrid, Spain Univ Complutense Madrid Madrid Spain E-28040 8040 Madrid, Spain
Citazione:
O. Hurtado et al., "Up-regulation of TNF-alpha convertase (TACE/ADAM17) after oxygen-glucose deprivation in rat forebrain slices", NEUROPHARM, 40(8), 2001, pp. 1094-1102

Abstract

Tumour necrosis factor-a (TNF-a) is a major immunomodulatory and proinflammatory cytokine which is shed in its soluble form by a membrane-anchored zinc protease, identified as a disintegrin and metalloproteinase (ADAM) called TNF-a convertase (TACE: ADAM17). The role of this protease in the adult nervous system remains poorly understood. During cerebral ischemia and subsequent reperfusion, expression and release of TNF-ol have been shown. We have investigated the expression and activity of TACE in an in vitro model of brain ischemia consisting of rat forebrain slices exposed to oxygen-glucosedeprivation (OGD). OGD caused the release of TNF-a, an effect which was inhibited by a hydroxamate-based metalloprotease inhibitor, BB-3103, with an IC50 of 0.1 muM. suggesting that TNF-alpha release results selectively fromTACE activity. Assay of TACE enzymatic activity on a fluorescein-labelled peptide spanning the cleavage site in pro-TNF-a, as well as Western blot and RT-PCR analyses showed that TACE is present in control forebrain and, more interestingly, that TACE expression is increased in OGD-exposed tissue. TACE enzymatic activity from OGD-exposed slices was significantly inhibited by cycloheximide, suggesting that de novo synthesis of TACE contributes to TNF-a release after ischaemia. Moreover, it was also inhibited by bisindolylmaleimide I, indicating that TACE activity is regulated by PKC. These findings posed the question of what was its function therein. Among other actions, TNF-a has been described to be involved in the expression of inducible nitric oxide synthase (iNOS), a high-output NOS isoform associated to cellular damage, but the link between TNF-a release after brain ischaemia and iNOS expression in this condition has not been shown. We have now found that iNOS expression in OGD-subjected brain slices is inhibited by BB-3103 at concentrations below 1 muM, indicating that shedding of TNF-a by TACE plays anecessary part in the induction of this NOS isoenzyme after OGD. Taken together, these data demonstrate that (1) TACE/ADAM 17 activity accounts for the majority of TNF-a shedding after OGD in rat forebrain slices, (2) an increase in TACE expression contributes, at least in part, to the rise in TNF-alpha. after OGD and (3) iNOS expression in OGD-subjected brain slices results from TACE activity and subsequent increase in TNF-a levels. (C) 2001 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 03/04/20 alle ore 14:19:56