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Overexpression of Bcl-2 by activated human hepatic stellate cells: resistance to apoptosis as a mechanism of progressive hepatic fibrogenesis in humans

¹ Dip Medicina e Oncologia Sperimentale, University of Torino, Italy
² Dip Medicina Interna-Centro di Ricerca, Trasferimento e Alta Formazione "DENOTHE", University of Florence, Italy

Correspondence to:
Correspondence to:
Professor M Parola
Università degli Studi di Torino, Dip Medicina e Oncologia Sperimentale, C so Raffaello 30, 10125 Torino, Italy; maurizio.parola{at}unito.it

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 (TNF-), 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- 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.

Abbreviations: CLDs, chronic liver diseases; DAPI, 4,6-diamidine-2-phenylindole di-hydrochloride; m, 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; NFB, nuclear factor B; PARP, poly (ADP ribose) polymerase; SFI medium, serum free Iscove’s medium; -SMA, smooth muscle actin; siRNA, small interfering RNA; TBS, Tris buffered saline; h-TERT, human telomerase catalytic subunit; TIMP, tissue inhibitor of metalloproteinases; TNF-, tumour necrosis factor ; TrkA, tyrosine kinase A

Keywords: activated human hepatic stellate cells; liver fibrosis; apoptosis; Bcl-2; induction of cell death

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Human hepatic stellate cells are resistant to apoptosis: implications for human fibrogenic liver disease

N Kawada
Gut 2006 55: 1073-1074. [Extract] [Full Text] [PDF]

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				N Kawada Human hepatic stellate cells are resistant to apoptosis: implications for human fibrogenic liver disease. Gut, August 1, 2006; 55(8): 1073 - 1074. [Full Text] [PDF]