Toll‐like receptors and adaptor molecules in liver disease: Update

Seki, Ekihiro; Brenner, David A.

doi:10.1002/hep.22306

Cited by 607 publications

(554 citation statements)

References 171 publications

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“…3,11 When primary human hepatocytes were challenged with E. coli, a 28-fold increase in IL-8 and a 17-fold increase in TNFa gene expression, as well as IL-8 secretion were observed. In contrast, neither IL-8 nor TNFa expression was found to be up-regulated in rAAV-transduced hepatocytes and no IL-8 was detected in cell culture supernatants (data not shown) indicating that rAAV does not induce innate immune responses in hepatocytes.…”

Section: Resultsmentioning

confidence: 99%

“…Among the critical sensors of viruses are Toll-like receptors (TLRs), retinoic acid-inducible gene I-like receptors and members of the nucleotidebinding and oligomerization domain like receptor family. 3 Upon ligand binding, signal transduction pathways are activated leading to the induction of inflammatory cytokines, chemokines and/or interferons (IFNs). 3 For AAV, the only PRR identified so far is TLR9, a PRR that senses DNA in endosomes.…”

mentioning

confidence: 99%

“…3 Upon ligand binding, signal transduction pathways are activated leading to the induction of inflammatory cytokines, chemokines and/or interferons (IFNs). 3 For AAV, the only PRR identified so far is TLR9, a PRR that senses DNA in endosomes. 4 This sensor is highly expressed on plasmacytoid dendritic cells (pDCs) that produce high levels of type I IFN in response to rAAV infection.…”

mentioning

confidence: 99%

“…Both hepatocytes as well as NPCs mount innate immune responses upon challenge with microorganisms, but differ in the repertoire of PRRs and consequently in the PAMPs that can be sensed. 3,5 To date, neither PRR(s) nor PAMP(s) have been identified recognizing rAAV in the liver, although this tissue is one of the main targets for human gene therapy.…”

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confidence: 99%

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Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors

et al. 2011

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors

et al. 2011

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“…Moreover, the magnitude of protection (ϷϪ40%) against fructose-induced hepatic steatosis found in livers of TLR-4 mutant mice fed fructose was similar to that reported earlier by our group for livers of fructose-fed mice treated with nonresorbable antibiotics. 10 Results of animal studies proposed the TLR-adapter proteins MyD88, IRF3, and IRF7 to be involved in mediating the effects of endotoxin [23][24][25] in Kupffer cells. Specifically, it has been shown that MyD88 is involved in the rapid activation of nuclear factor B (NF B) and the subsequent increase of TNF␣.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice

et al. 2009

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A link between dietary fructose intake, gut-derived endotoxemia, and nonalcoholic fatty liver disease (NAFLD) has been suggested by the results of human and animal studies. To further investigate the role of gut-derived endotoxin in the onset of fructose-induced NAFLD, Toll-like receptor (TLR-) 4-mutant (C3H/HeJ) mice and wildtype (C3H/HouJ) mice were either fed plain water or water enriched with 30% fructose for 8 weeks. Hepatic steatosis, plasma alanine aminotransferase (ALT), and markers of insulin resistance as well as portal endotoxin levels were determined. Hepatic levels of myeloid differentiation factor 88 (MyD88), interferon regulatory factor (IRF) 3 and 7, and tumor necrosis factor alpha (TNF␣) as well as markers of lipid peroxidation were assessed. Chronic intake of 30% fructose solution caused a significant increase in hepatic steatosis and plasma ALT levels in wildtype animals in comparison to water controls. In fructose-fed TLR-4 mutant mice, hepatic triglyceride accumulation was significantly reduced by Ϸ40% in comparison to fructose-fed wildtype mice and plasma ALT levels were at the level of water-fed controls. No difference in portal endotoxin concentration between fructose-fed wildtype and TLR-4-mutant animals was detected. In contrast, hepatic lipid peroxidation, MyD88, and TNF␣ levels were significantly decreased in fructose-fed TLR-4-mutant mice in comparison to fructose-fed wildtype mice, whereas IRF3 and IRF7 expression remained unchanged. Markers of insulin resistance (e.g., plasma TNF␣, retinol binding protein 4, and hepatic phospho-AKT) were only altered in fructose-fed wildtype animals. Conclusion: Taken together, these data further support the hypothesis that in mice the onset of fructose-induced NAFLD is associated with intestinal bacterial overgrowth and increased intestinal permeability, subsequently leading to an endotoxin-dependent activation of hepatic Kupffer cells.

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Hepatic Stellate Cells

Rojkind

Reyes‐Gordillo

2009

The Liver

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Toll‐like receptors and adaptor molecules in liver disease: Update

Cited by 607 publications

References 171 publications

Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors

Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors

Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice

Hepatic Stellate Cells

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