Objective: Defects in Fas-mediated apoptosis are supposed to contribute to the accumulation of T lymphocytes in the gut of patients with Crohn's disease (CD). This phenomenon has been functionally linked with the elevated expression of Flip, an inhibitor of Fas-mediated apoptosis. In this study, the molecular mechanisms that control Flip in CD were examined. Methods: Paired colonic biopsies of patients with CD, patients with ulcerative colitis (UC) and normal controls were analysed for Flip by real-time PCR and western blotting. Flip was also evaluated in CD3(+) lamina propria lymphocytes (T-LPLs) cultured with tosyl phenylalanyl chloromethyl ketone (TPCK; a nuclear factor-kappa B (NF-kappa B) inhibitor), AG490 (a Janus kinase 2 (Jak2)/signal transducer and activator of transcription (Stat) inhibitor) or 17-desmethoxy-17-N, N-dimethylamino-geldanamycin (DMAG; an inhibitor of heat shock protein 90). The rate of apoptosis was examined by flow cytometry. Results: In CD, upregulation of Flip occurred at both the RNA and protein level. Treatment of CD CD3(+) T-LPLs with TPCK or AG490 markedly reduced Flip RNA, suggesting a role for NF-kappa B and Jak/Stat pathways in the transcriptional control of Flip in this condition. Consistently, both TPCK and AG490 sensitised CD T-LPLs to Fas-mediated apoptosis. Flip protein in cells from normal gut was rapidly degraded by the proteasome pathway. In contrast, in inflamed gut of both CD and UC patients, there was a reduced degradation of Flip via the ubiquitin-proteasome-dependent pathway, but Flip expression can be decreased by DMAG. Conclusions: The data demonstrate that Flip is regulated at both the transcriptional and post-translational level in CD, and indicate that in the normal but not inflamed gut Flip is degraded via the ubiquitin-proteasome-dependent pathway.
|Tipologia:||Articolo su rivista|
|Citazione:||Caprioli, F., Stolfi, C., Caruso, R., Fina, D., Sica, G., Biancone, L., et al. (2008). Transcriptional and post-translational regulation of Flip, an inhibitor of Fas-mediated apoptosis, in human gut inflammation. GUT, 57(12), 1674-1680.|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore MED/12 - Gastroenterologia|
|Revisione (peer review):||Sì, ma tipo non specificato|
|Digital Object Identifier (DOI):||10.1136/gut.2008.149286|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2008|
|Titolo:||Transcriptional and post-translational regulation of Flip, an inhibitor of Fas-mediated apoptosis, in human gut inflammation|
|Autori interni:||SICA, GIUSEPPE |
|Autori:||Caprioli,F; Stolfi,C; Caruso, R; Fina, D; Sica,G; Biancone,L; Pallone,F; Monteleone,G|
|Appare nelle tipologie:||01 - Articolo su rivista|
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