Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice

2013 ◽  
Vol 58 (2) ◽  
pp. 342-349 ◽  
Author(s):  
Jin-Seok Byun ◽  
Yang-Gun Suh ◽  
Hyon-Seung Yi ◽  
Young-Sun Lee ◽  
Won-Il Jeong
Keyword(s):  
Liver Injury ◽  
Kupffer Cells ◽  
Stellate Cells ◽  
Interleukin 10 ◽  
Alcoholic Liver Injury ◽  
Toll Like Receptor

Selective activation of Toll-like receptor 7 in activated hepatic stellate cells may modulate their profibrogenic phenotype

2012 ◽  
Vol 447 (1) ◽  
pp. 25-34 ◽  
Author(s):  
Ming-Huei Chou ◽  
Ying-Hsien Huang ◽  
Tsun-Mei Lin ◽  
Yung-Ying Du ◽  
Po-Chin Tsai ◽  
...  
Keyword(s):  
Liver Injury ◽  
Obstructive Jaundice ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Toll Like Receptor ◽  
Selective Activation ◽  
Down Regulation ◽  
Duct Ligation ◽  
Cholestatic Liver Injury ◽  
Tgf Β1

Cholestatic liver injury may activate HSCs (hepatic stellate cells) to a profibrogenic phenotype, contributing to liver fibrogenesis. We have previously demonstrated the involvement of TLR (Toll-like receptor) 7 in the pathogenesis of biliary atresia. In the present study we investigated the ability of TLR7 to modulate the profibrogenic phenotype in HSCs. Obstructive jaundice was associated with significant down-regulation of TLR7. Primary HSCs isolated from BDL (bile duct ligation) rats with obstructive jaundice exhibited reduced expression of TLR7 and increased expression of α-SMA (α-smooth muscle actin) and collagen-α1 compared with sham rats, reflecting HSC-mediated changes. Treatment of primary activated rat HSCs and rat T6 cells with CL075, a TLR7 and TLR8 ligand, significantly decreased expression of MCP-1 (monocyte chemotactic protein-1), TGF-β1 (transforming growth factor-β1), collagen-α1 and MMP-2 (matrix metalloproteinase-2), and inhibited cell proliferation and migration. In contrast, silencing TLR7 expression with shRNA (short hairpin RNA) in T6 cells effectively blocked the effects of CL075 stimulation, reversing the changes in MCP-1, TGF-β1 and collagen-α1 expression and accelerating cell migration. Our results indicate that obstructive jaundice is associated with down-regulation of TLR7 and up-regulation of profibrogenic gene expression in HSCs. Selective activation of TLR7 may modulate the profibrogenic phenotype in activated HSCs associated with cholestatic liver injury.

scholarly journals The role of oxidative stress in alcoholic liver injury

2009 ◽  
Vol 62 (11-12) ◽  
pp. 547-553 ◽  
Author(s):  
Tatjana Radosavljevic ◽  
Dusan Mladenovic ◽  
Danijela Vucevic
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Liver Injury ◽  
Kupffer Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Alcoholic Liver Injury ◽  
Chronic Ethanol Consumption

Introduction. Oxidative stress plays an important role in pathogenesis of alcoholic liver injury. The main source of free oxygen species is cytochrome P450-dependent monooxygenase, which can be induced by ethanol. Role of cytochrome P4502E1 in ethanol-induced oxidative stress. Reactive oxygen species produced by this enzyme are more important in intracellular oxidative damage compared to species derived from activated phagocytes. Free radicals lead to lipid peroxidation, enzymatic inactivation and protein oxidation. Role of mitochondria in alcohol-induced oxidative stress. Production of mitochondrial reactive oxygen species is increased, and glutathione content is decreased in chronically ethanolfed animals. Oxidative stress in mitochondria leads to mitochondrial DNA damage and has a dual effect on apoptosis. Role of Kupffer cells in alcohol-induced liver injury. Chronic ethanol consumption is associated with increased release of endotoxin from gut lumen into portal circulation. Endotoxin activates Kupffer cells, which then release proinflammatory cytokines and oxidants. Role of neutrophils in alcohol-induced liver injury. Alcoholic liver injury leads to the accumulation of neutrophils, which release reactive oxygen species and lysosomal enzymes and contribute to hepatocyte damage and necrosis. Role of nitric oxide in alcohol-induced oxidative stress. High amounts of nitric oxide contribute to the oxidative damage, mainly by generating peroxynitrites. Role of antioxidants in ethanol-induced oxidative stress. Chronic ethanol consumption is associated with reduced liver glutathione and ?-tocopherol level and with reduced superoxide dismutase, catalase and glutathione peroxidase activity. Conclusion. Oxidative stress in alcoholic liver disease is a consequence of increased production of oxidants and decreased antioxidant defense in the liver.

scholarly journals Knockout of microRNA-21 attenuates alcoholic hepatitis through the VHL/NF-κB signaling pathway in hepatic stellate cells

2018 ◽  
Vol 315 (3) ◽  
pp. G385-G398 ◽  
Author(s):  
Nan Wu ◽  
Kelly McDaniel ◽  
Tianhao Zhou ◽  
Sugeily Ramos-Lorenzo ◽  
Chaodong Wu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Hepatic Stellate Cells ◽  
Liver Diseases ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Stellate Cells ◽  
Alcoholic Liver Injury ◽  
Human Hscs ◽  
Alcoholic Liver Diseases

microRNA-21 (miRNA) is one of the most abundant miRNAs in chronic liver injuries including alcoholic liver injury. Previous studies have demonstrated that miR-21 plays a role in inflammation in the liver and functions in hepatic stellate cells (HSCs), which reside in the perisinusoidal space between sinusoidal endothelial cells and hepatocytes and regulate sinusoidal circulation. HSCs integrate cytokine-mediated inflammatory responses in the sinusoids and relay them to the liver parenchyma. Here, we showed that the activation of Von Hippel-Lindau (VHL) expression, by miR-21 knockout in vivo and anti-miR-21 or VHL overexpression in vitro, suppressed the production of proinflammatory cytokines, such as interleukin (IL)-6, monocyte chemoattractant protein-1, and IL-1β, in human HSCs during alcoholic liver injury. Sequence and functional analyses confirmed that miR-21 directly targeted the 3′-untranslated region of VHL. Immunofluorescence and real-time PCR analysis revealed that miR-21 depletion blocked NF-κB activation in human HSCs both in cultured HSCs as well as HSCs isolated from alcohol-related liver disease mice liver by laser capture microdissection. We also showed that conditioned medium from anti-miR-21-transfected HSCs suppressed human monocyte-derived THP-1 cell migration. Taken together, our study indicates that depletion of miR-21 may downregulate cytokine production in HSCs and macrophage chemotaxis during alcoholic liver injury and that the targeting of miR-21 may have therapeutic potential for preventing the progression of alcoholic liver diseases. NEW & NOTEWORTHY This study demonstrates that silencing microRNA-21 can inhibit cytokine production and inflammatory responses in human hepatic stellate cells during alcoholic liver injury and that the targeting of microR-21 in hepatic stellate cells may have therapeutic potential for prevention and treatment of alcoholic liver diseases.

Role of Kupffer cells in failure of fatty livers following liver transplantation and alcoholic liver injury

1995 ◽  
Vol 10 (S1) ◽  
pp. S24-S30 ◽  
Author(s):  
RONALD G THURMAN ◽  
WENSHI GAO ◽  
HENRY D CONNOR ◽  
YUKITO ADACHI ◽  
ROBERT F STACHLEWITZ ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Liver Injury ◽  
Kupffer Cells ◽  
Alcoholic Liver Injury ◽  
Fatty Livers

287 Senescence of Activated Hepatic Stellate Cells Limits Liver Fibrosis During Alcoholic Liver Injury

2016 ◽  
Vol 150 (4) ◽  
pp. S1025
Author(s):  
Tianhao Zhou ◽  
Heather L. Francis ◽  
Ying Wan ◽  
Julie Venter ◽  
Nan Wu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Liver Injury ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Alcoholic Liver Injury ◽  
Activated Hepatic Stellate Cells

scholarly journals Kupffer cells modulate splenic interleukin-10 production in endotoxin-induced liver injury after partial hepatectomy

2003 ◽  
Vol 38 (2) ◽  
pp. 193-199 ◽  
Author(s):  
Kiyotaka Kurachi ◽  
Shohachi Suzuki ◽  
Takanori Sakaguchi ◽  
Yoshihiro Yokoi ◽  
Hiroyuki Konno ◽  
...  
Keyword(s):  
Liver Injury ◽  
Partial Hepatectomy ◽  
Kupffer Cells ◽  
Interleukin 10

Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation

2002 ◽  
Vol 283 (2) ◽  
pp. G256-G265 ◽  
Author(s):  
Grace L. Su
Keyword(s):  
Liver Injury ◽  
Proinflammatory Cytokines ◽  
Kupffer Cells ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Toll Like Receptor ◽  
Lipopolysaccharide Binding Protein ◽  
Toll Like Receptor 4 ◽  
Lipopolysaccharide Binding

Endogenous gut-derived bacterial lipopolysaccharides have been implicated as important cofactors in the pathogenesis of liver injury. However, the molecular mechanisms by which lipopolysaccharides exert their effect are not entirely clear. Recent studies have pointed to proinflammatory cytokines such as tumor necrosis factor-α as mediators of hepatocyte injury. Within the liver, Kupffer cells are major sources of proinflammatory cytokines that are produced in response to lipopolysaccharides. This review will focus on three important molecular components of the pathway by which lipopolysaccharides activate Kupffer cells: CD14, Toll-like receptor 4, and lipopolysaccharide binding protein. Within the liver, lipopolysaccharides bind to lipopolysaccharide binding protein, which then facilitates its transfer to membrane CD14 on the surface of Kupffer cells. Signaling of lipopolysaccharide through CD14 is mediated by the downstream receptor Toll-like receptor 4 and results in activation of Kupffer cells. The role played by these molecules in liver injury will be examined.

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