scholarly journals Kupffer cell activation by lipopolysaccharide in rats: Role for lipopolysaccharide binding protein and toll-like receptor 4

Hepatology ◽  
2000 ◽  
Vol 31 (4) ◽  
pp. 932-936 ◽  
Author(s):  
Grace L. Su ◽  
Richard D. Klein ◽  
Alireza Aminlari ◽  
Hong Y. Zhang ◽  
Lars Steinstraesser ◽  
...  
Keyword(s):  
Kupffer Cell ◽  
Cell Activation ◽  
Binding Protein ◽  
Toll Like Receptor ◽  
Lipopolysaccharide Binding Protein ◽  
Toll Like Receptor 4 ◽  
Lipopolysaccharide Binding

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.

scholarly journals Aging-related liver degeneration is associated with increased bacterial endotoxin and lipopolysaccharide binding protein levels

2020 ◽  
Vol 318 (4) ◽  
pp. G736-G747
Author(s):  
Cheng Jun Jin ◽  
Anja Baumann ◽  
Annette Brandt ◽  
Anna Janina Engstler ◽  
Anika Nier ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Damage ◽  
Binding Protein ◽  
Bacterial Endotoxin ◽  
Toll Like Receptor ◽  
Hepatic Inflammation ◽  
Lipopolysaccharide Binding Protein ◽  
Toll Like Receptor 4 ◽  
Liver Degeneration ◽  
Lipopolysaccharide Binding

Aging is a risk factor in the development of many diseases, including liver-related diseases. The two aims of the present study were 1) to determine how aging affects liver health in mice in the absence of any interventions and 2) if degenerations observed in relation to blood endotoxin levels are critical in aging-associated liver degeneration. Endotoxin levels and markers of liver damage, mitochondrial dysfunction, insulin resistance, and apoptosis as well as the Toll-like receptor 4 (Tlr-4) signaling cascade were studied in liver tissue and blood, respectively, of 3- and 24-mo-old male C57BL/6J mice. In a second set of experiments, 3- to 4-mo-old and 14-mo-old female lipopolysaccharide-binding protein (LBP)−/− mice and littermates fed standard chow, markers of liver damage, insulin resistance, and mitochondrial dysfunction were assessed. Plasma activity of aspartate aminotransferase and histological signs of hepatic inflammation and fibrosis were significantly higher in old C57BL/6J mice than in young animals. The number of neutrophils, CD8α-positive cells, and mRNA expression of markers of apoptosis were also significantly higher in livers of old C57BL/6J mice compared with young animals, being also associated with a significant induction of hepatic Tlr-4 and LBP expression as well as higher endotoxin levels in peripheral blood. Compared with age-matched littermates, LBP−/− mice display less signs of senescence in liver. Taken together, our data suggest that, despite being fed standard chow, old mice developed liver inflammation and beginning fibrosis and that bacterial endotoxin may play a critical role herein. NEW & NOTEWORTHY Old age in mice is associated with marked signs of liver degeneration, hepatic inflammation, and fibrosis. Aging-associated liver degeneration is associated with elevated bacterial endotoxin levels and an induction of lipopolysaccharide-binding protein (LBP) and Toll-like receptor 4-dependent signaling cascades in liver tissue. Furthermore, in old aged LBP−/− mice, markers of senescence seem to be lessened, supporting the hypothesis that bacterial endotoxin levels might be critical in aging-associated decline of liver.

scholarly journals Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury

Hepatology ◽  
2012 ◽  
Vol 55 (5) ◽  
pp. 1518-1528 ◽  
Author(s):  
Karim C. El Kasmi ◽  
Aimee L. Anderson ◽  
Michael W. Devereaux ◽  
Sophie A. Fillon ◽  
J. Kirk Harris ◽  
...  
Keyword(s):  
Liver Injury ◽  
Mouse Model ◽  
Parenteral Nutrition ◽  
Kupffer Cell ◽  
Cell Activation ◽  
Intestinal Injury ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Novel Roles in Human MD-2 of Phenylalanines 121 and 126 and Tyrosine 131 in Activation of Toll-like Receptor 4 by Endotoxin

2007 ◽  
Vol 283 (3) ◽  
pp. 1257-1266 ◽  
Author(s):  
Athmane Teghanemt ◽  
Fabio Re ◽  
Polonca Prohinar ◽  
Richard Widstrom ◽  
Theresa L. Gioannini ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Cell Activation ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Protein Protein Interactions ◽  
Lipopolysaccharide Binding Protein ◽  
Toll Like Receptor 4 ◽  
Dependent Cell ◽  
Cellular Responsiveness ◽  
Tlr4 Activation

Potent mammalian cell activation by Gram-negative bacterial endotoxin requires sequential protein-endotoxin and protein-protein interactions involving lipopolysaccharide-binding protein, CD14, MD-2, and Toll-like receptor 4 (TLR4). TLR4 activation requires simultaneous binding of MD-2 to endotoxin (E) and the ectodomain of TLR4. We now describe mutants of recombinant human MD-2 that bind TLR4 and react with E·CD14 but do not support cellular responsiveness to endotoxin. The mutants F121A/K122A MD-2 and Y131A/K132A MD-2 react with E·CD14 only when co-expressed with TLR4. Single mutants K122A and K132A each react with E·CD14 ± TLR4 and promote TLR4-dependent cell activation by endotoxin suggesting that Phe121 and Tyr131 are needed for TLR4-independent transfer of endotoxin from CD14 to MD-2 and also needed for TLR4 activation by bound E·MD-2. The mutant F126A MD-2 reacts as well as wild-type MD-2 with E·CD14 ± TLR4. E·MD-2F126A binds TLR4 with high affinity (Kd ∼ 200 pm) but does not activate TLR4 and instead acts as a potent TLR4 antagonist, inhibiting activation of HEK/TLR4 cells by wild-type E·MD-2. These findings reveal roles of Phe121 and Tyr131 in TLR4-independent interactions of human MD-2 with E·CD14 and, together with Phe126, in activation of TLR4 by bound E·MD-2. These findings strongly suggest that the structural properties of E·MD-2, not E alone, determine agonist or antagonist effects on TLR4.

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