Article

TLR4, Ethanol, and Lipid Rafts: A New Mechanism of Ethanol Action with Implications for other Receptor-Mediated Effects

Louisiana State University in Shreveport, Shreveport, Louisiana, United States
The Journal of Immunology (Impact Factor: 4.92). 03/2007; 178(3):1243-9. DOI: 10.4049/jimmunol.178.3.1243
Source: PubMed

ABSTRACT

Ethanol (EtOH) is the most widely abused substance in the United States, and it contributes to well-documented harmful (at high dosages) and beneficial (at low dosages) changes in inflammatory and immune responses. Lipid rafts have been implicated in the regulation and activation of several important receptor complexes in the immune system, including the TLR4 complex. Many questions remain about the precise mechanisms by which rafts regulate the assembly of these receptor complexes. Results summarized in this review indicate that EtOH acts by altering the LPS-induced redistribution of components of the TLR4 complex within the lipid raft and that this is related to changes in actin cytoskeleton rearrangement, receptor clustering, and subsequent signaling. EtOH provides an example of an immunomodulatory drug that acts at least in part by modifying lipid rafts, and it could represent a model to probe the relationships between rafts, receptor complexes, and signaling.

Download full-text

Full-text

Available from: Stephen Pruett
  • Source
    • "Our findings suggest that the TGF-b enhancer activity of ethanol is responsible, at least in part, for the disease. These results may also explain the broad spectrum of ethanol-related pathologies because, like cholesterol-depleting agents [Chen et al., 2007, 2008], ethanol causes structural and functional alterations of lipid rafts/caveolae [Dolganiuc et al., 2006; Szabo et al., 2007], resulting in displacement of TGF-b receptors and other important membrane receptors from lipid rafts/caveolae and their translocation to non-lipid raft microdomains. The lipid rafts/caveolae are utilized as signaling platforms by many membrane proteins (e.g., neurotransmitter receptors and G protein-coupled receptors) to mediate important physiological processes [Luo and Miller, 1999; Ghiselli et al., 2003; Hiney et al., 2003; Radek et al., 2008; Assaife-Lopes et al., 2010; Nothdurfter et al., 2013; Cuddy et al., 2014]. "

    Full-text · Dataset · Nov 2015
  • Source
    • "Our findings suggest that the TGF-b enhancer activity of ethanol is responsible, at least in part, for the disease. These results may also explain the broad spectrum of ethanol-related pathologies because, like cholesterol-depleting agents [Chen et al., 2007, 2008], ethanol causes structural and functional alterations of lipid rafts/caveolae [Dolganiuc et al., 2006; Szabo et al., 2007], resulting in displacement of TGF-b receptors and other important membrane receptors from lipid rafts/caveolae and their translocation to non-lipid raft microdomains. The lipid rafts/caveolae are utilized as signaling platforms by many membrane proteins (e.g., neurotransmitter receptors and G protein-coupled receptors) to mediate important physiological processes [Luo and Miller, 1999; Ghiselli et al., 2003; Hiney et al., 2003; Radek et al., 2008; Assaife-Lopes et al., 2010; Nothdurfter et al., 2013; Cuddy et al., 2014]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Regular consumption of moderate amounts of ethanol has important health benefits on atherosclerotic cardiovascular disease (ASCVD). Overindulgence can cause many diseases, particularly alcoholic liver disease (ALD). The mechanisms by which ethanol causes both beneficial and harmful effects on human health are poorly understood. Here we demonstrate that ethanol enhances TGF-β-stimulated luciferase activity with a maximum of 0.5-1% (v/v) in Mv1Lu cells stably expressing a luciferase reporter gene containing Smad2-dependent elements. In Mv1Lu cells, 0.5% ethanol increases the level of P-Smad2, a canonical TGF-β signaling sensor, by ∼2-3-fold. Ethanol (0.5%) increases cell-surface expression of the type II TGF-β receptor (TβR-II) by ∼2-3-fold from its intracellular pool, as determined by I(125) -TGF-β-cross-linking/Western blot analysis. Sucrose density gradient ultracentrifugation and indirect immunofluorescence staining analyses reveal that ethanol (0.5 and 1%) also displaces cell-surface TβR-I and TβR-II from lipid rafts/caveolae and facilitates translocation of these receptors to non-lipid raft microdomains where canonical signaling occurs. These results suggest that ethanol enhances canonical TGF-β signaling by increasing non-lipid raft microdomain localization of the TGF-β receptors. Since TGF-β plays a protective role in ASCVD but can also cause ALD, the TGF-β enhancer activity of ethanol at low and high doses appears to be responsible for both beneficial and harmful effects. Ethanol also disrupts the location of lipid raft/caveolae of other membrane proteins (e.g., neurotransmitter, growth factor/cytokine and G protein-coupled receptors) which utilize lipid rafts/caveolae as signaling platforms. Displacement of these membrane proteins induced by ethanol may result in a variety of pathologies in nerve, heart and other tissues. This article is protected by copyright. All rights reserved.
    Full-text · Article · Sep 2015 · Journal of Cellular Biochemistry
  • Source
    • "Recent results have demonstrated that recognition of TLR expressed by macrophages or other cell types plays a key role in initiating inflammation, especially in ethanol consumption [8] [9] [10] [11]. TLR4 is the receptor of LPS which activates the downstream signals and various transcription factors in nuclear, such as STAT3, leading to International Immunopharmacology 17 (2013) 184–190 Abbreviations: BA, betulinic acid; BT, betulin; HSCs, hepatic stellate cells; α-SMA, α-smooth muscle actin; LPS, lipopolysaccharide; TLR4, Toll-like receptor4; STAT3, signal transducer and activator of transcription 3; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TG, serum triglyceride; CYP2E1, cytochrome P4502E1; SREBP-1c, sterol regulatory element-binding protein-1c. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ethanol consumption leads to many kinds of liver injury and suppresses innate immunity, but the molecular mechanisms have not been fully delineated. The present study was conducted to determine whether betulinic acid (BA) or betulin (BT) would ameliorate acute ethanol-induced fatty liver in mice, and to characterize whether Toll like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) were involved in ethanol-stimulated hepatic stellate cells (HSCs). EtOH (5mg/kg) and BA or BT (20 or 50mg/kg) were applied in vivo, while EtOH (50mM) and BA or BT (12.5 or 25μM) were applied in vitro. Administration of BA or BT significantly prevented the increases of serum ALT and AST caused by ethanol, as well as serum TG. Supplement of BA or BT prevented ethanol-induced acidophilic necrosis, increased hepatocyte nuclei and stromal inflammation infiltration as indicated by liver histopathological studies. Administration of BA or BT significantly decreased CYP2E1 activities and expression of SREBP-1caused by ethanol, however, lower dosage of BA or BT showed slight effects on CYP2E1 activity or expression of SREBP-1c. BA or BT administration significantly decreased the expression of TLR4, and increased the phosphorylation of STAT3. In vitro, BA or BT treatment reduced the expressions of α-SMA and collagen-I in ethanol-stimulated HSCs via regulation of TLR4 and STAT3, coincided with in vivo. All of these findings demonstrated that BA or BT might ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro, promising agents for ethanol-induced fatty liver therapies.
    Full-text · Article · Jun 2013 · International immunopharmacology
Show more