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Articles 1 - 17 of 17
Full-Text Articles in Gastroenterology
Complement Factor D Protects Mice From Ethanol-Induced Inflammation And Liver Injury., Rebecca L Mccullough, Megan R Mcmullen, Megan M Sheehan, Kyle L Poulsen, Sanjoy Roychowdhury, Dian J Chiang, Michele T Pritchard, Juan Caballeria, Laura E Nagy
Complement Factor D Protects Mice From Ethanol-Induced Inflammation And Liver Injury., Rebecca L Mccullough, Megan R Mcmullen, Megan M Sheehan, Kyle L Poulsen, Sanjoy Roychowdhury, Dian J Chiang, Michele T Pritchard, Juan Caballeria, Laura E Nagy
Articles, Abstracts, and Reports
Complement plays a crucial role in microbial defense and clearance of apoptotic cells. Emerging evidence suggests complement is an important contributor to alcoholic liver disease. While complement component 1, Q subcomponent (C1q)-dependent complement activation contributes to ethanol-induced liver injury, the role of the alternative pathway in ethanol-induced injury is unknown. Activation of complement via the classical and alternative pathways was detected in alcoholic hepatitis patients. Female C57BL/6J [wild type (WT)], C1q-deficient ( C1qa
Gut-Liver Axis In Alcoholic Liver Disease, Gyongyi Szabo
Gut-Liver Axis In Alcoholic Liver Disease, Gyongyi Szabo
Gyongyi Szabo
Alcoholic liver disease (ALD) has been among the leading causes of cirrhosis and liver-related death worldwide for decades. Early discoveries in alcoholic liver disease identified increased levels of bacterial endotoxin in the portal circulation, suggesting a role for gut-derived toxins in ALD. Indeed, alcohol consumption can disrupt the intestinal epithelial barrier and result in increased gut permeability that increasingly is recognized as a major factor in ALD. Bacterial endotoxin, lipopolysaccharide, is a prototypic microbe-derived inflammatory signal that contributes to inflammation in ALD through activation of the Toll-like receptor 4. Recent studies also have shown that alcohol consumption is associated with …
Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo
Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo
Katherine A. Fitzgerald
Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of …
Binge Ethanol And Liver: New Molecular Developments, Shivendra Shukla, Stephen Pruett, Gyongyi Szabo, Gavin Arteel
Binge Ethanol And Liver: New Molecular Developments, Shivendra Shukla, Stephen Pruett, Gyongyi Szabo, Gavin Arteel
Gyongyi Szabo
Binge consumption of alcohol is an alarming global health problem. Binge (acute) ethanol (EtOH) is implicated in the pathophysiology of alcoholic liver disease (ALD). New studies from experimental animals and from humans indicate that binge EtOH has profound effects on immunological, signaling, and epigenetic parameters of the liver. This is in addition to the known metabolic effects of acute EtOH. Binge EtOH alters the levels of several cellular components and dramatically amplifies liver injury in chronically EtOH exposed liver. These studies highlight the importance of molecular investigations into binge effects of EtOH for a better understanding of ALD and also …
Toll-Like Receptors In Liver Disease, Jan Petrasek, Timea Csak, Gyongyi Szabo
Toll-Like Receptors In Liver Disease, Jan Petrasek, Timea Csak, Gyongyi Szabo
Gyongyi Szabo
Activation of inflammatory signaling pathways is of central importance in the pathogenesis of alcoholic liver disease (ALD) and nonalcoholic steatohepatitis (NASH). 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 and NASH. In this review, we emphasize the importance of gut-derived endotoxin and its recognition by TLR4 in the liver. The significance of TLR-induced intracellular signaling pathways and cytokine production as well as the contribution of individual cell types to the inflammation is …
Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo
Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo
Gyongyi Szabo
Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of …
Microrna Signature In Alcoholic Liver Disease, Shashi Bala, Gyongyi Szabo
Microrna Signature In Alcoholic Liver Disease, Shashi Bala, Gyongyi Szabo
Gyongyi Szabo
Alcoholic liver disease (ALD) is a major global health problem. Chronic alcohol use results in inflammation and fatty liver, and in some cases, it leads to fibrosis and cirrhosis or hepatocellular carcinoma. Increased proinflammatory cytokines, particularly TNF alpha, play a central role in the pathogenesis of ALD. TNF alpha is tightly regulated at transcriptional and posttranscriptional levels. Recently, microRNAs (miRNAs) have been shown to modulate gene functions. The role of miRNAs in ALD is getting attention, and recent studies suggest that alcohol modulates miRNAs. Recently, we showed that alcohol induces miR-155 expression both in vitro (RAW 264.7 macrophage) and in …
An Essential Role For Monocyte Chemoattractant Protein-1 In Alcoholic Liver Injury: Regulation Of Proinflammatory Cytokines And Hepatic Steatosis In Mice, Pranoti Mandrekar, Aditya Ambade, Arlene Lim, Gyongyi Szabo, Donna Catalano
An Essential Role For Monocyte Chemoattractant Protein-1 In Alcoholic Liver Injury: Regulation Of Proinflammatory Cytokines And Hepatic Steatosis In Mice, Pranoti Mandrekar, Aditya Ambade, Arlene Lim, Gyongyi Szabo, Donna Catalano
Gyongyi Szabo
The importance of chemokines in alcoholic liver injury has been implicated. The role of the chemokine, monocyte chemoattractant protein-1 (MCP-1), elevated in patients with alcoholic liver disease is not yet understood. Here, we evaluated the pathophysiological significance of MCP-1 and its receptor, chemokine (C-C motif) receptor 2 (CCR2), in alcoholic liver injury. The Leiber-DeCarli diet containing alcohol or isocaloric control diets were fed to wild-type (WT) and MCP-1-deficient knockout (KO) mice for 6 weeks. In vivo and in vitro assays were performed to study the role of MCP-1 in alcoholic liver injury. MCP-1 was increased in Kupffer cells (KCs) as …
Interferon Regulatory Factor 3 And Type I Interferons Are Protective In Alcoholic Liver Injury In Mice By Way Of Crosstalk Of Parenchymal And Myeloid Cells, Jan Petrasek, Angela Dolganiuc, Timea Csak, Bharath Nath, Istvan Hritz, Karen Kodys, Donna Catalano, Evelyn Kurt-Jones, Pranoti Mandrekar, Gyongyi Szabo
Interferon Regulatory Factor 3 And Type I Interferons Are Protective In Alcoholic Liver Injury In Mice By Way Of Crosstalk Of Parenchymal And Myeloid Cells, Jan Petrasek, Angela Dolganiuc, Timea Csak, Bharath Nath, Istvan Hritz, Karen Kodys, Donna Catalano, Evelyn Kurt-Jones, Pranoti Mandrekar, Gyongyi Szabo
Gyongyi Szabo
Alcoholic liver disease (ALD) features increased hepatic exposure to bacterial lipopolysaccharide (LPS). Toll-like receptor-4 (TLR4) recognizes LPS and activates signaling pathways depending on MyD88 or TRIF adaptors. We previously showed that MyD88 is dispensable in ALD. TLR4 induces Type I interferons (IFNs) in an MyD88-independent manner that involves interferon regulatory factor-3 (IRF3). We fed alcohol or control diets to wild-type (WT) and IRF3 knock-out (KO) mice, and to mice with selective IRF3 deficiency in liver parenchymal and bone marrow-derived cells. Whole-body IRF3-KO mice were protected from alcohol-induced liver injury, steatosis, and inflammation. In contrast to WT or bone marrow-specific IRF3-KO …
Innate Immunity And Alcoholic Liver Disease, Bin Gao, Ekihiro Seki, Jessica Cohen, Laura Nagy, Gyongyi Szabo, Samir Zakhari
Innate Immunity And Alcoholic Liver Disease, Bin Gao, Ekihiro Seki, Jessica Cohen, Laura Nagy, Gyongyi Szabo, Samir Zakhari
Gyongyi Szabo
Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, while activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates …
Up-Regulation Of Microrna-155 In Macrophages Contributes To Increased Tumor Necrosis Factor {Alpha} (Tnf{Alpha}) Production Via Increased Mrna Half-Life In Alcoholic Liver Disease, Shashi Bala, Miguel Marcos, Karen Kodys, Timea Csak, Donna Catalano, Pranoti Mandrekar, Gyongyi Szabo
Up-Regulation Of Microrna-155 In Macrophages Contributes To Increased Tumor Necrosis Factor {Alpha} (Tnf{Alpha}) Production Via Increased Mrna Half-Life In Alcoholic Liver Disease, Shashi Bala, Miguel Marcos, Karen Kodys, Timea Csak, Donna Catalano, Pranoti Mandrekar, Gyongyi Szabo
Gyongyi Szabo
Activation of Kupffer cells (KCs) by gut-derived lipopolysaccharide (LPS) and Toll-Like Receptors 4 (TLR4)-LPS-mediated increase in TNFalpha production has a central role in the pathogenesis of alcoholic liver disease. Micro-RNA (miR)-125b, miR-146a, and miR-155 can regulate inflammatory responses to LPS. Here we evaluated the involvement of miRs in alcohol-induced macrophage activation. Chronic alcohol treatment in vitro resulted in a time-dependent increase in miR-155 but not miR-125b or miR-146a levels in RAW 264.7 macrophages. Furthermore, alcohol pretreatment augmented LPS-induced miR-155 expression in macrophages. We found a linear correlation between alcohol-induced increase in miR-155 and TNFalpha induction. In a mouse model of …
Alcoholic Liver Disease And The Gut-Liver Axis, Gyongyi Szabo, Shashi Bala
Alcoholic Liver Disease And The Gut-Liver Axis, Gyongyi Szabo, Shashi Bala
Gyongyi Szabo
Alcoholic liver disease (ALD) is one of the leading causes of liver diseases and liver-related death worldwide. Of the many factors that contribute to the pathogenesis of ALD, gut-derived lipopolysaccharide (LPS) plays a central role in induction of steatosis, inflammation, and fibrosis in the liver. In this review, we discuss the mechanisms by which alcohol contributes to increased gut permeability, the activation of Kupffer cells, and the inflammatory cascade by LPS. The role of the Toll-like receptor 4 (TLR4) complex in LPS recognition and the importance of the TLR4-induced signaling pathways are evaluated in ALD.
Rsa 2004: Combined Basic Research Satellite Symposium - Session Two: Toll-Like Receptors And Organ Damage, Pranoti Mandrekar, Stephen Pruett, Gavin Arteel, Geoffrey Thiele, Gyongyi Szabo
Rsa 2004: Combined Basic Research Satellite Symposium - Session Two: Toll-Like Receptors And Organ Damage, Pranoti Mandrekar, Stephen Pruett, Gavin Arteel, Geoffrey Thiele, Gyongyi Szabo
Gyongyi Szabo
This article summarizes the proceedings of the RSA 2004 Combined Basic Research Satellite Meeting convened at the Westin Bayshore Resort and Marina, Vancouver, BC. The session "Toll-like receptors and organ damage" featured three speakers and was chaired by Drs. Steve Nelson and Craig McClain. The presentations were 1) Toll-like receptor mediated macrophage activation-modulation by acute alcohol administration in mice by Stephen Pruett, 2) Alcoholic liver disease: Crossroads of TLRs and oxidative stress by Gavin Arteel, and 3) The role of TLR2 and TLR4-mediated signals in liver injury by Gyongyi Szabo.
Alcohol-Induced Modulation Of Signaling Pathways In Liver Parenchymal And Nonparenchymal Cells: Implications For Immunity, Bharath Nath, Gyongyi Szabo
Alcohol-Induced Modulation Of Signaling Pathways In Liver Parenchymal And Nonparenchymal Cells: Implications For Immunity, Bharath Nath, Gyongyi Szabo
Gyongyi Szabo
Alcoholic liver injury involves a complex array of derangements in cellular signaling of hepatic parenchymal and nonparenchymal cells as well as cells of the immune system. In the hepatocyte, chronic ethanol abuse leads to lipid accumulation and liver steatosis. Multiple pathways are affected to promote lipid accumulation in the ethanol-exposed hepatocyte. Chronic ethanol renders Kupffer cells hyperresponsive to endotoxin, which results in production of inflammatory cytokines and the tumor necrosis factor-alpha via a toll-like receptor 4 dependent pathway, leading to inflammation and hepatic necrosis. Dysfunction of the innate and adaptive immune responses caused by ethanol contributes to impaired antiviral response, …
Moderate Drinking, Inflammation, And Liver Disease, Gyongyi Szabo
Moderate Drinking, Inflammation, And Liver Disease, Gyongyi Szabo
Gyongyi Szabo
It is well known that heavy drinking increases the risk of alcohol-related liver disease (ALD). Female gender, hepatitis C or B, obesity, and other cofactors increase susceptibility to ALD, so “safe” levels of alcohol consumption in regard to ALD vary among individuals. Inflammation is one mechanism by which alcohol causes liver damage. Increasing evidence suggests that in contrast to the proinflammatory activation by chronic excessive alcohol consumption, acute moderate alcohol administration has anti-inflammatory effects. Long-term alcohol administration results in increased baseline nuclear regulatory factor κB (NF-κB) activation in the livers of mice; in contrast, acute alcohol administration in mice attenuates …
The Critical Role Of Toll-Like Receptor (Tlr) 4 In Alcoholic Liver Disease Is Independent Of The Common Tlr Adapter Myd88, Istvan Hritz, Pranoti Mandrekar, Arumugam Velayudham, Donna Catalano, Angela Dolganiuc, Karen Kodys, Evelyn Kurt-Jones, Gyongyi Szabo
The Critical Role Of Toll-Like Receptor (Tlr) 4 In Alcoholic Liver Disease Is Independent Of The Common Tlr Adapter Myd88, Istvan Hritz, Pranoti Mandrekar, Arumugam Velayudham, Donna Catalano, Angela Dolganiuc, Karen Kodys, Evelyn Kurt-Jones, Gyongyi Szabo
Gyongyi Szabo
The Toll-like receptor 4 (TLR4) that recognizes endotoxin, a trigger of inflammation in alcoholic liver disease (ALD), activates two signaling pathways utilizing different adapter molecules: the common TLR adapter, myeloid differentiation factor 88 (MyD88), or Toll/interleukin immune-response-domain-containing adaptor inducing interferon (IFN)-beta. The MyD88 pathway induces proinflammatory cytokine activation, a critical mediator of ALD. Here we evaluated the role of MyD88 in alcohol-induced liver injury in wild-type, TLR2-deficient, TLR4-deficient, or MyD88-deficient (knockout [KO]) mice after administration of the Lieber-De-Carli diet (4.5% volume/volume ethanol) or an isocaloric liquid control diet for 5 weeks. Alcohol feeding resulted in a significant increase in serum …
Pathogenic Interactions Between Alcohol And Hepatitis C, Gyongyi Szabo
Pathogenic Interactions Between Alcohol And Hepatitis C, Gyongyi Szabo
Gyongyi Szabo
Alcohol is the most commonly abused substance in the United States, and alcohol abuse leads to alcoholic liver disease, a long recognized major public health concern. The high prevalence of chronic hepatitis C virus (HCV) infection, along with the clinical observation that HCV infection is common in alcoholic patients presenting with liver disease, has directed attention to the interaction between alcohol and HCV infection. Clinical studies have identified alcohol use as an independent risk factor for progression of fibrosis in chronic HCV infection. Experimental evidence suggests additive inhibitory effects between HCV and alcohol on antiviral immune responses. In addition, specific …