Overexpression of Bcl-2 by activated human hepatic stellate cells: resistance to apoptosis as a mechanism of progressive hepatic fibrogenesis in humans. Issue 8 (19th January 2006)

• Record Type: Journal Article
• Authors: Novo, E; Marra, F; Zamara, E; Valfrè di Bonzo, L; Monitillo, L; Cannito, S; Petrai, I; Mazzocca, A; Bonacchi, A; De Franco, R S M; Colombatto, S; Autelli, R; Pinzani, M; Parola, M
• Is Part Of: Gut. Volume 55:Issue 8(2006)
• Page Start: 1174
• Page End: 1182
• Publication Date: 2006-01-19
• Subjects: CLDs, chronic liver diseases -- DAPI, 4, 6-diamidine-2-phenylindole di-hydrochloride -- Δψm, mitochondrial membrane potential -- ECL, enhanced chemiluminescence -- ERK, extracellular regulated kinase -- FasL, Fas ligand -- HCV, hepatitis C virus -- HSC, hepatic stellate cells -- HSC/MFs, activated hepatic stellate cells in myofibroblast-like phenotype -- JC-1, J-aggregate forming lipophilic cation -- LDH, lactate dehydrogenase -- mAb, monoclonal antibody -- NGF, nerve growth factor -- NFκB, nuclear factor κB -- PARP, poly (ADP ribose) polymerase -- SFI medium, serum free Iscove's medium -- α-SMA, α smooth muscle actin -- siRNA, small interfering RNA -- TBS, Tris buffered saline -- h-TERT, human telomerase catalytic subunit -- TIMP, tissue inhibitor of metalloproteinases -- TNF-α, tumour necrosis factor α -- TrkA, tyrosine kinase A; activated human hepatic stellate cells -- liver fibrosis -- apoptosis -- Bcl-2 -- induction of cell death; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2005.082701
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background and aims: Myofibroblast-like cells, originating from activation of hepatic stellate cells (HSC/MFs), play a key role in liver fibrosis, a potentially reversible process that may rely on induction of HSC/MFs apoptosis. While this possibility has been shown in cultured rat HSC, very limited data are currently available for human HSC/MFs. Methods: Cultured human HSC/MFs were exposed to several proapoptotic stimuli, including those known to induce apoptosis in rat HSC/MFs, and induction of cell death and related mechanisms were investigated using morphology, molecular biology, and biochemical techniques. Results: In this study we report that fully activated human HSC/MFs did not undergo spontaneous apoptosis and survived to prolonged serum deprivation, Fas activation, or exposure to nerve growth factor, tumour necrosis factor α (TNF-α), oxidative stress mediators, doxorubicin, and etoposide. Induction of caspase dependent, mitochondria driven apoptosis in HSC/MFs was observed only when protein synthesis or transcription were inhibited. Importantly, the process of HSC activation was accompanied by changes in expression of a set of genes involved in apoptosis control. In particular, activated human HSC/MFs in culture overexpressed Bcl-2. The role of Bcl-2 was crucial as Bcl-2 silenced cells became susceptible to TNF-α induced apoptosis. Finally, Bcl-2 was markedly expressed in HSC/MFs present in liver tissue obtained from patients with hepatitis C virus related cirrhosis. Conclusions: Human activated HSC/MFs are resistant to most proapoptotic stimuli due to Bcl-2 overexpression and this feature may play a key role in the progression of fibrosis in chronic liver diseases.