Smads 2 and 3 Are Differentially Activated by Transforming Growth Factor-β (TGF-β) in Quiescent and Activated Hepatic Stellate Cells

Liu, Chenghai; Gaça, Marianna; Swenson, E. Scott; Vellucci, Vincent F.; Reiß, Michael; Wells, Rebecca G.

doi:10.1074/jbc.m207728200

Cited by 182 publications

(158 citation statements)

References 73 publications

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“…These cells, when activated, produce and secrete cytokines; cytokines may be proinflammatory, such as TNF-a and IL-1, or profibrotic, such as TGF-b. These proteins can further increase ROS and play important roles in the mediation of hepatic injury [23,[85][86][87], such as fatty liver, by inhibiting lipase of lipoprotein and adiponectin and fibrosis as a result of HSC activation [88][89][90].…”

Section: Viral Hepatitis and Free Radicalsmentioning

confidence: 99%

Role of free radicals in liver diseases

2009

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Reactive oxygen and nitrogen species (ROS and RNS) are produced by metabolism of normal cells. However, in liver diseases, redox is increased thereby damaging the hepatic tissue; the capability of ethanol to increase both ROS/RNS and peroxidation of lipids, DNA, and proteins was demonstrated in a variety of systems, cells, and species, including humans. ROS/RNS can activate hepatic stellate cells, which are characterized by the enhanced production of extracellular matrix and accelerated proliferation. Cross-talk between parenchymal and nonparenchymal cells is one of the most important events in liver injury and fibrogenesis; ROS play an important role in fibrogenesis throughout increasing platelet-derived growth factor. Most hepatocellular carcinomas occur in cirrhotic livers, and the common mechanism for hepatocarcinogenesis is chronic inflammation associated with severe oxidative stress; other risk factors are dietary aflatoxin B 1 consumption, cigarette smoking, and heavy drinking. Ischemia-reperfusion injury affects directly on hepatocyte viability, particularly during transplantation and hepatic surgery; ischemia activates Kupffer cells which are the main source of ROS during the reperfusion period. The toxic action mechanism of paracetamol is focused on metabolic activation of the drug, depletion of glutathione, and covalent binding of the reactive metabolite N-acetyl-pbenzoquinone imine to cellular proteins as the main cause of hepatic cell death; intracellular steps critical for cell death include mitochondrial dysfunction and, importantly, the formation of ROS and peroxynitrite. Infection with hepatitis C is associated with increased levels of ROS/RNS and decreased antioxidant levels. As a consequence, antioxidants have been proposed as an adjunct therapy for various liver diseases.

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Section: Viral Hepatitis and Free Radicalsmentioning

confidence: 99%

Role of free radicals in liver diseases

2009

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“…Primary HSCs were isolated from the male retired breeder Sprague-Dawley rats and cultured as described previously. 21,32 All work with animals was approved by the University of Pennsylvania Institutional Animal Care and Use Committee and done in accordance with National Institutes of Health guidelines. All the cells used in any given experiment in which PFs or HSCs were studied over time were isolated from a single animal.…”

Section: Methodsmentioning

confidence: 99%

Transforming growth factor-β and substrate stiffness regulate portal fibroblast activation in culture

et al. 2007

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Myofibroblasts derived from portal fibroblasts are important fibrogenic cells in the early stages of biliary fibrosis. In contrast to hepatic stellate cells, portal fibroblasts have not been well studied in vitro, and little is known about their myofibroblastic differentiation. In this article we report the isolation and characterization of rat portal fibroblasts in culture. We demonstrate that primary portal fibroblasts undergo differentiation to ␣-smooth muscle actin-expressing myofibroblasts over 10 -14 days. Marker analysis comparing portal fibroblasts to hepatic stellate cells demonstrated that these are distinct populations and that staining with elastin and desmin can differentiate between them. Portal fibroblasts expressed elastin at all stages in culture but never expressed desmin, whereas hepatic stellate cells consistently expressed desmin but never elastin. Immunostaining of rat liver tissue confirmed these results in vivo. Characterization of portal fibroblast differentiation in culture demonstrated that these cells required transforming growth factor-␤ (TGF-␤): cells remained quiescent in the presence of a TGF-␤ receptor kinase inhibitor, whereas exogenous TGF-␤1 enhanced portal fibroblast ␣-smooth muscle actin expression and stress fiber formation. In contrast, platelet-derived growth factor inhibited myofibroblastic differentiation. Portal fibroblasts were also dependent on mechanical tension for myofibroblastic differentiation, and cells cultured on polyacrylamide supports of variable stiffness demonstrated an increasingly myofibroblastic phenotype as stiffness increased. Conclusion: Portal fibroblasts are morphologically and functionally distinct from hepatic stellate cells. Portal fibroblast myofibroblastic differentiation can be modeled in culture and requires both TGF-␤ and mechanical tension. (HEPATOLOGY 2007;46:1246-1256

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“…The method described previously was modified per Liu et al 14 Mice were anesthetized, and in situ liver perfusion and digestion were performed with pronase E (2.4 mg/mL; Roche Molecular Biochemicals, Chicago, IL) and collagenase B (0.3-0.45 mg/ml; Roche Molecular Biochemicals, Branchburg, NJ), and the resulting liver cell suspension was purified via density gradient centrifugation using 9%-11% Nycodenz (Sigma-Aldrich, St. Louis, MO). HSCs were plated on standard tissue culture plastic dishes in M199 medium with 10% fetal bovine serum at a density of 1 ϫ 10 6 per 1-cm plate and maintained in M199/10% fetal bovine serum supplemented with glutamine and antibiotics [penicillin, 100 U/mL; streptomycin, 100 U/mL; gentamicin, 0.1 mg/mL; and fungizone, 2.5 g/mL (Invitrogen, Carlsbad, CA)].…”

Section: Methodsmentioning

confidence: 99%

Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9

et al. 2007

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Apoptosis of hepatocytes results in the development of liver fibrosis, but the molecular signals mediating this are poorly understood. Degradation and modification of nuclear DNA is a central feature of apoptosis, and DNA from apoptotic mammalian cells is known to activate immune cells via Toll-like receptor 9 (TLR9). We tested if DNA from apoptotic hepatocytes can induce hepatic stellate cell (HSC) differentiation. Our data show that apoptotic hepatocyte DNA and cytidine-phosphate-guanosine oligonucleotides induced up-regulation of transforming growth factor ␤1 and collagen 1 messenger RNA both in the human HSC line LX-2 and in primary mouse HSCs. These effects were opposed by TLR9 antagonists. We have recently shown that adenosine inhibits HSC chemotaxis, and we now show that apoptotic hepatocyte DNA also inhibits platelet-derived growth factor (PDGF)-mediated HSC chemotaxis.

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Smads 2 and 3 Are Differentially Activated by Transforming Growth Factor-β (TGF-β) in Quiescent and Activated Hepatic Stellate Cells

Cited by 182 publications

References 73 publications

Role of free radicals in liver diseases

Role of free radicals in liver diseases

Transforming growth factor-β and substrate stiffness regulate portal fibroblast activation in culture

Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9

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