Transcriptional and post-translational regulation of Flip, an inhibitor of Fas-mediated apoptosis, in human gut inflammation

Caprioli, F; StoIfi, C; Caruso, R; Fina, D; Sica, G; Biancone, L; Pallone, F; Monteleone, G
December 2008
Gut;Dec2008, Vol. 57 Issue 12, p1674
Academic Journal
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 blothng. Flip was also evaluated in CD3~ lamina propria lymphocytes (T-LPLs) cultured with tosyl phenylalanyl chloromethyl ketone (TPCK; a nuclear factor-KB (NF-KB) inhibitor), AG490 (a Janus kinase 2 (Jak2)/signal transducer and activator of transcription (Stat) inhibitor( or 1 7-desmethoxy-1 7-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-KB and Jal~'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.


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