Stellate cell apoptosis by a soluble mediator from immortalized human hepatocytes.
Activated hepatic stellate cells (HSCs) are the major source of extracellular matrix in fibrosis and cirrhosis. In this study, we have investigated the role of hepatitis C virus (HCV) core protein induced immortalized human hepatocytes (IHH) on HSC growth. Preferential growth of IHH and apoptosis of activated human hepatic stellate cells (LX2) were observed upon coculture of these two cell types in a dual chamber or in the presence of conditioned medium (CM) from IHH. CM did not display a growth inhibitory role on other hepatic (Huh-7, HepG2, Hep3B and THLE) and non-hepatic (HeLa, MCF-7, and BHK) epithelial cells, indicating that the soluble mediator from IHH does not have a generalized effect on cell lines examined in our study. Further studies suggested that CM from IHH increased the expression of TRAIL receptors on LX2 cell surface, and induced apoptosis by a caspase dependent mechanism. Peptide mass fingerprinting of the purified soluble mediator from CM suggested that gelsolin fragments may play a role in apoptosis of LX2 cells. Taken together, our results suggested that a soluble mediator secreted from immortalized human hepatocytes plays an important role in hepatic stellate cell growth regulation.
Basu
Arnab
A
Department of Internal Medicine, Saint Louis University, St. Louis, MO 63110, USA.
Saito
Kousuke
K
Meyer
Keith
K
Ray
Ratna B
RB
Friedman
Scott L
SL
Chang
Yie-Hwa
YH
Ray
Ranjit
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016466:CHO Cells; D053181:Caspase 8 / Q000502:physiology; D006224:Cricetinae; D017077:Culture Media, Conditioned / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000502:physiology; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D007093:Imidazoles; D008099:Liver / Q000166:cytology*; D009952:Ornithine / Q000031:analogs & derivatives; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis; D015398:Signal Transduction; D019714:Tissue Inhibitor of Metalloproteinases / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014758:Viral Core Proteins / Q000502:physiology
D017077:Culture Media, Conditioned; D053222:Fas Ligand Protein; D007093:Imidazoles; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C107968:N(delta)-(5-methyl-4-oxo-2-imidazolin-2-yl)ornithine; D009952:Ornithine; D053181:Caspase 8