Toll-Like Receptors in the Pathogenesis of Alcoholic Liver Disease

Department of Medicine, University of Massachusetts Medical School, LRB215, 364 Plantation Street, Worcester, MA 01605, USA.
Gastroenterology Research and Practice (Impact Factor: 1.75). 08/2010; 2010(1687-6121). DOI: 10.1155/2010/710381
Source: PubMed


In the multifactorial pathophysiology of alcoholic liver disease (ALD), inflammatory cascade activation plays a central role. Recent studies demonstrated that Toll-like Receptors, the sensors of microbial and endogenous danger signals, are expressed and activated in innate immune cells as well as in parenchymal cells in the liver and thereby contribute to ALD. In this paper, we discuss the importance of gut-derived endotoxin and its recognition by TLR4. The significance of TLR-induced intracellular signaling pathways and cytokine production as well as the contribution of reactive oxygen radicals is evaluated. The contribution of TLR signaling to induction of liver fibrosis and hepatocellular cancer is reviewed in the context of alcohol-induced liver disease.

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Available from: Gyongyi Szabo
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    • "Bacterial translocation due to disruption of the gut-barrier function by alcohol induces endotoxemia [4]. Activation of the toll-like receptor-4 (TLR-4)-mediated signaling pathway, proinflammatory cytokines, and the reactive oxygen species induced by endotoxins [lipopolysaccharide (LPS)] are important factors in the pathogenesis of ALD [5]. Although multiple medications have been proposed as potential therapeutic * Corresponding author. "
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    ABSTRACT: Background Roles of immune reaction and toll-like receptor-4 (TLR-4) have widely been established in the pathogenesis of alcoholic liver disease (ALD). Methods We evaluated the biologic efficacy of Korean Red Ginseng (KRG), urushiol, and probiotics (Lactobacillus rhamnosus R0011 and Lactobacillus acidophilus R0052) in mouse models of ALD. Sixty C57BL/6 mice were equally divided into six feeding groups for 10 weeks: normal diet, alcohol, control, alcohol + KRG, alcohol + urushiol, and alcohol + probiotics. Alcohol was administered via a Lieber–DeCarli liquid diet containing 10% alcohol. TLR-4 expression, proinflammatory cytokines, and histology, as well as the results of liver function tests were evaluated and compared. Results No between-group differences were observed with regard to liver function. TLR-4 levels were significantly lower in the KRG, urushiol, and probiotics groups than in the alcohol group (0.37 ± 0.06 ng/mL, 0.39 ± 0.12 ng/mL, and 0.33 ± 0.07 ng/mL, respectively, vs. 0.88 ± 0.31 ng/mL; p < 0.05). Interleukin-1β levels in liver tissues were decreased among the probiotics and KRG groups. The tumor necrosis factor-α level of liver tissue was decreased in the KRG group. Conclusion The pathological findings showed that alcohol-induced steatosis was significantly reduced by KRG and urushiol. As these agents improve immunologic capacity, they may be considered in potential anti-ALD treatments.
    Full-text · Article · Jul 2014 · Journal of ginseng research
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    • "TLRs have been implicated in liver fibrosis, resulting from many common liver diseases, including viral, parasitic and toxin-induced hepatitis. Early reports implicated the release of intestinal LPS into the portal circulation in alcohol-induced liver injury and cirrhosis [56, 57]. Subsequent reports showed that TLR4 mediates inflammation and fibrosis in bile duct ligation and toxin-induced models of liver fibrosis [58]. "
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    ABSTRACT: Recent advances in our understanding of innate immunity and inflammation have direct bearing on how we understand autoimmunity, and fibrosis, and how innate immune sensors might stimulate both of these key features of several fibrotic diseases. Toll-like receptors (TLRs) are the major receptors for recognizing pathogen associated molecular patterns present on bacterial cell walls, such as LPS, and nucleic acids (RNA and DNA). Several intracellular pathways mediate TLR effects and initiate various pro-inflammatory programs. Mechanisms for control of inflammation, matrix remodeling, and ultimately fibrosis are also activated. Transforming growth factor-beta (TGF-β), Interleukin-1 (IL-1), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-13 (IL-13), and interferon (IFNs) appear particularly important in regulating pro-fibrotic aspects of innate immune activation. These mechanisms appear important in fibrotic disease affecting multiple organ-systems, including lung, liver, kidney, and skin. These observations provide new paradigms for understanding the relationship between immunity/inflammation and fibrosis, however, the precise ligand and mechanism linking innate immune sensor(s) to fibrosis remain uncertain in most illnesses.
    Full-text · Article · Jun 2012 · The Open Rheumatology Journal
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    • "LPS stimulates different cells in the liver to release cytokines/chemokines, and reactive oxygen species (ROS) via Toll-like receptor 4 (TLR4)-mediated mechanisms (Hritz et al., 2008, Mandrekar and Szabo, 2009). In addition to TLR4, other TLRs may play a role in liver hypersensitivity to LPS and other gut-derived pathogen-associated molecules (Gustot et al., 2006, Petrasek et al., 2010). "
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    ABSTRACT: Interactions between the gut, immune system, and the liver, as well as the type of fat in the diet, are critical components of alcoholic liver disease (ALD). The goal of the present study was to determine the effects of saturated fat (SF) and unsaturated fat (USF) on ethanol (EtOH)-induced gut-liver interactions in a mouse model of ALD. C57BL/6N mice were fed Lieber-DeCarli liquid diets containing EtOH and enriched in USF (corn oil) or SF (medium chain triglycerides:beef tallow). Control mice were pair-fed on an isocaloric basis. Liver injury and steatosis, blood endotoxin levels, intestinal permeability, and tight junction (TJ) integrity, as well as hepatic Toll-like receptor (TLR) gene expression, were evaluated. After 8 weeks of EtOH feeding, liver injury and steatosis were observed in USF + EtOH group compared with control and SF + EtOH. Significantly increased intestinal permeability in conjunction with elevated blood endotoxin levels were observed in the ileal segments of the mice fed USF + EtOH. USF diet alone resulted in down-regulation of intestinal TJ protein mRNA expression compared with SF. Importantly, alcohol further suppressed TJ proteins in USF + EtOH, but did not affect intestinal TJ in SF + EtOH group. The type of fat in the diet alone did not affect hepatic TLR expression. Compared with control animals, hepatic TLR (TLR 1, 2, 3, 4, 7, 8, 9) mRNA expression was significantly (p < 0.05) increased in USF + EtOH, but not in SF + EtOH group. Notably, TLR5 was the only up-regulated TLR in both SF + EtOH and USF + EtOH groups. Dietary fat is an important cofactor in alcohol-associated liver injury. We demonstrate that USF (corn oil/linoleic acid) by itself results in dysregulation of intestinal TJ integrity leading to increased gut permeability, and alcohol further exacerbates these alterations. We postulate that elevated blood endotoxin levels in response to USF and alcohol in conjunction with up-regulation of hepatic TLRs combine to cause hepatic injury in ALD.
    Full-text · Article · Dec 2011 · Alcoholism Clinical and Experimental Research
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