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Full-Text Articles in Hepatology

Tumor Biology And Immune Infiltration Define Primary Liver Cancer Subsets Linked To Overall Survival After Immunotherapy, Anuradha Budhu, Erica C Pehrsson, Aiwu He, Lipika Goyal, Robin Kate Kelley, Hien Dang, Changqing Xie, Cecilia Monge, Mayank Tandon, Lichun Ma, Mahler Revsine, Laura Kuhlman, Karen Zhang, Islam Baiev, Ryan Lamm, Keyur Patel, David E Kleiner, Stephen M Hewitt, Bao Tran, Jyoti Shetty, Xiaolin Wu, Yongmei Zhao, Tsai-Wei Shen, Sulbha Choudhari, Yuliya Kriga, Kris Ylaya, Andrew C Warner, Elijah F Edmondson, Marshonna Forgues, Tim F Greten, Xin Wei Wang Jun 2023

Tumor Biology And Immune Infiltration Define Primary Liver Cancer Subsets Linked To Overall Survival After Immunotherapy, Anuradha Budhu, Erica C Pehrsson, Aiwu He, Lipika Goyal, Robin Kate Kelley, Hien Dang, Changqing Xie, Cecilia Monge, Mayank Tandon, Lichun Ma, Mahler Revsine, Laura Kuhlman, Karen Zhang, Islam Baiev, Ryan Lamm, Keyur Patel, David E Kleiner, Stephen M Hewitt, Bao Tran, Jyoti Shetty, Xiaolin Wu, Yongmei Zhao, Tsai-Wei Shen, Sulbha Choudhari, Yuliya Kriga, Kris Ylaya, Andrew C Warner, Elijah F Edmondson, Marshonna Forgues, Tim F Greten, Xin Wei Wang

Kimmel Cancer Center Faculty Papers

Primary liver cancer is a rising cause of cancer deaths in the US. Although immunotherapy with immune checkpoint inhibitors induces a potent response in a subset of patients, response rates vary among individuals. Predicting which patients will respond to immune checkpoint inhibitors is of great interest in the field. In a retrospective arm of the National Cancer Institute Cancers of the Liver: Accelerating Research of Immunotherapy by a Transdisciplinary Network (NCI-CLARITY) study, we use archived formalin-fixed, paraffin-embedded samples to profile the transcriptome and genomic alterations among 86 hepatocellular carcinoma and cholangiocarcinoma patients prior to and following immune checkpoint inhibitor treatment. …


Hepatitis C Virus-Induced Monocyte Differentiation Into Polarized M2 Macrophages Promotes Stellate Cell Activation Via Tgf-Beta, Banishree Saha, Karen Kodys, Gyongyi Szabo May 2017

Hepatitis C Virus-Induced Monocyte Differentiation Into Polarized M2 Macrophages Promotes Stellate Cell Activation Via Tgf-Beta, Banishree Saha, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND and AIMS: Monocyte and macrophage (MPhi) activation contributes to the pathogenesis of chronic hepatitis C virus (HCV) infection. Disease pathogenesis is regulated by both liver-resident MPhis and monocytes recruited as precursors of MPhis into the damaged liver. Monocytes differentiate into M1 (classic/proinflammatory) or M2 (alternative/anti-inflammatory) polarized MPhis in response to tissue microenvironment. We hypothesized that HCV-infected hepatoma cells (infected with Japanese fulminant hepatitis-1 [Huh7.5/JFH-1]) induce monocyte differentiation into polarized MPhis. METHODS: Healthy human monocytes were co-cultured with Huh7.5/JFH-1 cells or cell-free virus for 7 days and analyzed for MPhi markers and cytokine levels. A similar analysis was performed on …


Progression Of Non-Alcoholic Steatosis To Steatohepatitis And Fibrosis Parallels Cumulative Accumulation Of Danger Signals That Promote Inflammation And Liver Tumors In A High Fat-Cholesterol-Sugar Diet Model In Mice, Michal Ganz, Terence N. Bukong, Timea Csak, Banishree Saha, Jin-Kyu Park, Aditya Ambade, Karen Kodys, Gyongyi Szabo Sep 2015

Progression Of Non-Alcoholic Steatosis To Steatohepatitis And Fibrosis Parallels Cumulative Accumulation Of Danger Signals That Promote Inflammation And Liver Tumors In A High Fat-Cholesterol-Sugar Diet Model In Mice, Michal Ganz, Terence N. Bukong, Timea Csak, Banishree Saha, Jin-Kyu Park, Aditya Ambade, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming a pandemic. While multiple 'hits' have been reported to contribute to NAFLD progression to non-alcoholic steatohepatitis (NASH), fibrosis and liver cancer, understanding the natural history of the specific molecular signals leading to hepatocyte damage, inflammation and fibrosis, is hampered by the lack of suitable animal models that reproduce disease progression in humans. The purpose of this study was first, to develop a mouse model that closely mimics progressive NAFLD covering the spectrum of immune, metabolic and histopathologic abnormalities present in human disease; and second, to characterize the temporal relationship between sterile/exogenous danger …


Inhibition Of Sterile Danger Signals, Uric Acid And Atp, Prevents Inflammasome Activation And Protects From Alcoholic Steatohepatitis In Mice., Arvin Iracheta-Vellve, Jan Petrasek, Abhishek Satishchandran, Benedek Gyongyosi, Banishree Saha, Karen Kodys, Katherine Fitzgerald, Evelyn Kurt-Jones, Gyongyi Szabo Aug 2015

Inhibition Of Sterile Danger Signals, Uric Acid And Atp, Prevents Inflammasome Activation And Protects From Alcoholic Steatohepatitis In Mice., Arvin Iracheta-Vellve, Jan Petrasek, Abhishek Satishchandran, Benedek Gyongyosi, Banishree Saha, Karen Kodys, Katherine Fitzgerald, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

Background & Aims: The inflammasome is a well-characterized inducer of inflammation in alcoholic steatohepatitis (ASH). Inflammasome activation requires two signals for mature interleukin (IL)-1β production. Here we asked whether metabolic danger signals trigger inflammasome activation in ASH.

Results:The sterile danger signals, ATP and uric acid, were increased in the serum and liver of alcohol-fed mice. Depletion of uric acid or ATP, or lack of ATP signaling attenuated ASH and prevented inflammasome activation and its major downstream cytokine, IL-1β. Pharmacological depletion of uric acid with allopurinol provided significant protection from alcohol-induced inflammatory response, steatosis and liver damage, and additional protection was …


Metabolic Danger Signals, Uric Acid And Atp, Mediate Inflammatory Cross-Talk Between Hepatocytes And Immune Cells In Alcoholic Liver Disease., Jan Petrasek, Arvin Iracheta-Vellve, Banishree Saha, Abhishek Satishchandran, Karen Kodys, Katherine Fitzgerald, Evelyn Kurt-Jones, Gyongyi Szabo Aug 2015

Metabolic Danger Signals, Uric Acid And Atp, Mediate Inflammatory Cross-Talk Between Hepatocytes And Immune Cells In Alcoholic Liver Disease., Jan Petrasek, Arvin Iracheta-Vellve, Banishree Saha, Abhishek Satishchandran, Karen Kodys, Katherine Fitzgerald, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

Inflammation defines the progression of ALD from reversible to advanced stages. Translocation of bacterial LPS to the liver from the gut is necessary for alcohol-induced liver inflammation. However, it is not known whether endogenous, metabolic danger signals are required for inflammation in ALD. Uric acid and ATP, 2 major proinflammatory danger signals, were evaluated in the serum of human volunteers exposed to a single dose of ethanol or in supernatants of primary human hepatocytes exposed to ethanol. In vitro studies were used to evaluate the role of uric acid and ATP in inflammatory cross-talk between hepatocytes and immune cells. The …


Alcohol And Hcv: Implications For Liver Cancer, Gyongyi Szabo, Banishree Saha, Terence Bukong Jun 2015

Alcohol And Hcv: Implications For Liver Cancer, Gyongyi Szabo, Banishree Saha, Terence Bukong

Gyongyi Szabo

Liver cancers are one of the deadliest known malignancies which are increasingly becoming a major public health problem in both developed and developing countries. Overwhelming evidence suggests a strong role of infection with hepatitis B and C virus (HBV and HCV), alcohol abuse, as well as metabolic diseases such as obesity and diabetes either individually or synergistically to cause or exacerbate the development of liver cancers. Although numerous etiologic mechanisms for liver cancer development have been advanced and well characterized, the lack of definite curative treatments means that gaps in knowledge still exist in identifying key molecular mechanisms and pathways …


Alcohol-Induced Mir-27a Regulates Differentiation And M2 Macrophage Polarization Of Normal Human Monocytes, Banishree Saha, Johanna Bruneau, Karen Kodys, Gyongyi Szabo May 2015

Alcohol-Induced Mir-27a Regulates Differentiation And M2 Macrophage Polarization Of Normal Human Monocytes, Banishree Saha, Johanna Bruneau, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

Alcohol abuse is a leading cause of liver disease characterized by liver inflammation, fatty liver, alcoholic hepatitis, or liver cirrhosis. Immunomodulatory effects of alcohol on monocytes and macrophages contribute to alcoholic liver disease. Alcohol use, an independent risk factor for progression of hepatitis C virus (HCV) infection-mediated liver disease, impairs host defense and alters cytokine production and monocyte/macrophage activation. We hypothesized that alcohol and HCV have synergistic effects on the phenotype and function of monocytes. Our data show that acute alcohol binge drinking in healthy volunteers results in increased frequency of CD16(+) and CD68(+) and M2-type (CD206(+), dendritic cell [DC]-SIGN(+)-expressing …


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 Sep 2014

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 …


Chronic Alcohol-Induced Microrna-155 Contributes To Neuroinflammation In A Tlr4-Dependent Manner In Mice, Dora Lippai, Shashi Bala, Timea Csak, Evelyn A. Kurt-Jones, Gyongyi Szabo Sep 2014

Chronic Alcohol-Induced Microrna-155 Contributes To Neuroinflammation In A Tlr4-Dependent Manner In Mice, Dora Lippai, Shashi Bala, Timea Csak, Evelyn A. Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

INTRODUCTION: Alcohol-induced neuroinflammation is mediated by pro-inflammatory cytokines and chemokines including tumor necrosis factor-alpha (TNFalpha), monocyte chemotactic protein-1 (MCP1) and interleukin-1-beta (IL-1beta). Toll-like receptor-4 (TLR4) pathway induced nuclear factor-kappaB (NF-kappaB) activation is involved in the pathogenesis of alcohol-induced neuroinflammation. Inflammation is a highly regulated process. Recent studies suggest that microRNAs (miRNAs) play crucial role in fine tuning gene expression and miR-155 is a major regulator of inflammation in immune cells after TLR stimulation. AIM: To evaluate the role of miR-155 in the pathogenesis of alcohol-induced neuroinflammation. METHODS: Wild type (WT), miR-155- and TLR4-knockout (KO) mice received 5% ethanol-containing or isocaloric …


Another Armed Cd4(+) T Cell Ready To Battle Hepatocellular Carcinoma, Roniel Cabrera, Gyongyi Szabo Sep 2014

Another Armed Cd4(+) T Cell Ready To Battle Hepatocellular Carcinoma, Roniel Cabrera, Gyongyi Szabo

Gyongyi Szabo

No abstract provided.


Human Ezrin-Moesin-Radixin Proteins Modulate Hepatitis C Virus Infection, Terence Bukong, Karen Kodys, Gyongyi Szabo Sep 2014

Human Ezrin-Moesin-Radixin Proteins Modulate Hepatitis C Virus Infection, Terence Bukong, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

Host cytoskeletal proteins of the ezrin-moesin-radixin (EMR) family have been shown to modulate single-stranded RNA virus infection through regulating stable microtubule formation. Antibody engagement of CD81, a key receptor for hepatitis C virus (HCV) entry, induces ezrin phosphorylation. Here we tested the role of EMR proteins in regulating HCV infection and explored potential therapeutic targets. We show that HCV E2 protein induces rapid ezrin phosphorylation and its cellular redistribution with F-actin by way of spleen tyrosine kinase (SYK). Therapeutically blocking the functional roles of SYK or F-actin reorganization significantly reduced Huh7.5 cell susceptibility to HCV J6/JFH-1 infection. Using gene regulation, …


Differences In Innate Immune Signaling Between Alcoholic And Non-Alcoholic Steatohepatitis, Jan Petrasek, Timea Csak, Michal Ganz, Gyongyi Szabo Sep 2014

Differences In Innate Immune Signaling Between Alcoholic And Non-Alcoholic Steatohepatitis, Jan Petrasek, Timea Csak, Michal Ganz, Gyongyi Szabo

Gyongyi Szabo

The similar histopathological characteristics of alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH), and the crucial role of the innate immune response in both conditions may lead to the assumption that ASH and NASH represent the same pathophysiological entities caused by different risk factors. In this review paper, we elaborate on the pathophysiological differences between these two entities and highlight the disease-specific involvement of signaling molecules downstream of the Toll-like receptor 4, and the differential mechanism by which the inflammasome contributes to ASH versus NASH. Our findings emphasize that ASH and NASH have disease-specific mechanisms and therefore represent distinct biological entities. …


Micro-Rna-155 Deficiency Prevents Alcohol-Induced Serum Endotoxin Increase And Small Bowel Inflammation In Mice, Dora Lippai, Shashi Bala, Donna Catalano, Karen Kodys, Gyongyi Szabo Sep 2014

Micro-Rna-155 Deficiency Prevents Alcohol-Induced Serum Endotoxin Increase And Small Bowel Inflammation In Mice, Dora Lippai, Shashi Bala, Donna Catalano, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND: Chronic alcohol impairs gut barrier function and induces inflammatory cytokines. The effects of acute alcohol binge on the gut are partially understood. Micro-RNA-155 (miR-155), a modulator of cytokine and T-cell immune response in the gut, stabilizes tumor necrosis factor-alpha (TNFalpha) mRNA. Here, we investigated the role of the inflammation modulator miR-155 as well as the effects of acute binge and chronic alcohol feeding in the small bowel (SB) in mice. METHODS: For the acute alcohol binge, wild-type (WT) mice received 5 g/kg 50% alcohol/d or equal amount of water oral gavage for 3 days. WT and miR-155-deficient (miR-155-knockout [KO]) …


Human Type 2 Myeloid Dendritic Cells Produce Interferon-Lambda And Amplify Interferon-Alpha In Response To Hepatitis C Virus Infection, Shuye Zhang, Karen Kodys, Kui Li, Gyongyi Szabo Sep 2014

Human Type 2 Myeloid Dendritic Cells Produce Interferon-Lambda And Amplify Interferon-Alpha In Response To Hepatitis C Virus Infection, Shuye Zhang, Karen Kodys, Kui Li, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND and AIMS: The type III interferons (IFN-lambdas: interleukin [IL]-28a, IL-28b, and IL-29) have important roles in hepatitis C virus (HCV) infection, but little is understood about what cells produce these cytokines or how production is activated. We investigated whether human immune cells recognize HCV-infected cells and respond by producing IFN-lambda. METHODS: We cultured healthy human peripheral blood mononuclear cells (PBMCs) with different populations of immune cells and Japanese fulminant hepatitis-1 (JFH-1) HCV-infected Huh7.5 (cell culture-derived HCV particles [HCVcc]/Huh7.5) cells. RESULTS: Human PBMCs recognized HCVcc/Huh7.5 cells and responded by producing IFN-alpha, IFN-gamma, and IFN-lambda. A rare subset of myeloid dendritic …


Converging Actions Of Alcohol On Liver And Brain Immune Signaling, Gyongyi Szabo, Dora Lippai Sep 2014

Converging Actions Of Alcohol On Liver And Brain Immune Signaling, Gyongyi Szabo, Dora Lippai

Gyongyi Szabo

Chronic excessive alcohol consumption results in inflammation in multiple organs, including the brain. While the contribution of neuroinflammation to alcohol-related cognitive dysfunction and behavioral alterations is established, the mechanisms by which alcohol triggers inflammation in the brain are only partially understood. There are acute and long-term alterations in brain function due to intercellular and intracellular changes of different cell types as a result of alcohol consumption. This review focuses on the alcohol-induced proinflammatory cellular and molecular changes in the central nervous system. Alcohol passes through the blood-brain barrier and alters neurotransmission. Alcohol use activates microglia and astrocyte, contributing to neurodegeneration …


Both Bone Marrow-Derived And Non-Bone Marrow-Derived Cells Contribute To Aim2 And Nlrp3 Inflammasome Activation In A Myd88-Dependent Manner In Dietary Steatohepatitis, Timea Csak, Arun Pillai, Michal Ganz, Dora Lippai, Jan Petrasek, Jin-Kyu Park, Karen Kodys, Angela Dolganiuc, Evelyn Kurt-Jones, Gyongyi Szabo Sep 2014

Both Bone Marrow-Derived And Non-Bone Marrow-Derived Cells Contribute To Aim2 And Nlrp3 Inflammasome Activation In A Myd88-Dependent Manner In Dietary Steatohepatitis, Timea Csak, Arun Pillai, Michal Ganz, Dora Lippai, Jan Petrasek, Jin-Kyu Park, Karen Kodys, Angela Dolganiuc, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND and AIMS: Inflammation promotes the progression of non-alcoholic steatohepatitis (NASH). Toll-like receptor 4 (TLR4) and TLR9 activation through myeloid differentiation primary response gene 88 (MyD88) and production of mature interleukin-1beta (IL-1beta) via inflammasome activation contribute to steatohepatitis. Here, we investigated the inter-relationship between TLR signalling and inflammasome activation in dietary steatohepatitis.

METHODS: Wild type (WT), TLR4- and MyD88-deficient (KO) mice received methionine-choline-deficient (MCD) or -supplemented (MCS) diets for 5 weeks and a subset was challenged with TLR9 ligand CpG-DNA.

RESULTS: TLR4, TLR9, AIM2 (absent in melanoma 2) and NLRP3 (NLR family pyrin domain containing 3) inflammasome mRNA, and mature …


Toll-Like Receptors In Liver Disease, Jan Petrasek, Timea Csak, Gyongyi Szabo Sep 2014

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 …


Exosome-Mediated Delivery Of Functionally Active Mirna-155 Inhibitor To Macrophages, Fatemeh Momen-Heravi, Shashi Bala, Terence Bukong, Gyongyi Szabo Sep 2014

Exosome-Mediated Delivery Of Functionally Active Mirna-155 Inhibitor To Macrophages, Fatemeh Momen-Heravi, Shashi Bala, Terence Bukong, Gyongyi Szabo

Gyongyi Szabo

Exosomes, membranous nanovesicles, naturally carry bio-macromolecules and play pivotal roles in both physiological intercellular crosstalk and disease pathogenesis. Here, we showed that B cell-derived exosomes can function as vehicles to deliver exogenous miRNA-155 mimic or inhibitor into hepatocytes or macrophages, respectively. Stimulation of B cells significantly increased exosome production. Unlike in parental cells, baseline level of miRNA-155 was very low in exosomes derived from stimulated B cells. Exosomes loaded with a miRNA-155 mimic significantly increased miRNA-155 levels in primary mouse hepatocytes and the liver of miRNA-155 knockout mice. Treatment of RAW macrophages with miRNA-155 inhibitor loaded exosomes resulted in statistically …


High Fat Diet Feeding Results In Gender Specific Steatohepatitis And Inflammasome Activation, Michal Ganz, Timea Csak, Gyongyi Szabo Sep 2014

High Fat Diet Feeding Results In Gender Specific Steatohepatitis And Inflammasome Activation, Michal Ganz, Timea Csak, Gyongyi Szabo

Gyongyi Szabo

AIM: To develop an animal model that encompasses the different facets of non-alcoholic steatohepatitis (NASH), which has been a challenge. METHODS: In this study, we used a high fat diet (HFD) feeding supplemented with fructose and sucrose in the water mimicking the high-fructose corn syrup that is abundant in the diet in the United States. We used C57Bl/6 wild-type mice for short and long-term feedings of 6 and 16 wk respectively, and evaluated the extent of liver damage, steatosis, and inflammasome activation. Our methods included histopathological analysis to assess liver damage and steatosis, which involved H and E and oil-red-o …


Immune And Inflammatory Pathways In Nash, Michal Ganz, Gyongyi Szabo Sep 2014

Immune And Inflammatory Pathways In Nash, Michal Ganz, Gyongyi Szabo

Gyongyi Szabo

Immune and inflammatory pathways have a central role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Both the innate and adaptive immune systems contribute to the development of NAFLD. Pathogen-associated molecular patterns and danger-associated molecular patterns are known to activate a variety of pattern-recognition receptors that result in inflammation. The key features of the immune system and inflammatory pathways in the development of NAFLD are discussed in this review.


Innate Immune Cell Networking In Hepatitis C Virus Infection, Banishree Saha, Gyongyi Szabo Sep 2014

Innate Immune Cell Networking In Hepatitis C Virus Infection, Banishree Saha, Gyongyi Szabo

Gyongyi Szabo

Persistent viral infection, such as HCV infection, is the result of the inability of the host immune system to mount a successful antiviral response, as well as the escape strategies devised by the virus. Although each individual component of the host immune system plays important roles in antiviral immunity, the interactive network of immune cells as a whole acts against the virus. The innate immune system forms the first line of host defense against viral infection, and thus, virus elimination or chronic HCV infection is linked to the direct outcome of the interactions between the various innate immune cells and …


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 Sep 2014

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 …


Ifn-Gamma Production By Human Natural Killer Cells In Response To Hcv-Infected Hepatoma Cells Is Dependent On Accessory Cells, Shuye Zhang, Banishree Saha, Karen Kodys, Gyongyi Szabo Jun 2013

Ifn-Gamma Production By Human Natural Killer Cells In Response To Hcv-Infected Hepatoma Cells Is Dependent On Accessory Cells, Shuye Zhang, Banishree Saha, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND and AIMS: Interferon-gamma (IFN-gamma), a cytokine produced by activated natural killer cell (NK) and T lymphocytes, is an important regulator of innate and adaptive immunity during hepatitis C virus (HCV) infection. However, the cellular sources and mechanisms of IFN-gamma induction in HCV-infection are not fully understood. METHODS: We cultured normal human peripheral blood mononuclear cells (PBMCs) with different populations of immune cells and JFH-1 HCV-infected Huh7.5 (JFH-1/Huh7.5) cells. RESULTS: We found that PBMCs produced large amounts of IFN-gamma after co-culture with JFH-1/Huh7.5 cells. Using intracellular cytokine staining we confirmed that NK cells and NKT cells (to a lesser extent) …


Human Monoclonal Antibody Mbl-Hcv1 Delays Hcv Viral Rebound Following Liver Transplantation: A Randomized Controlled Study, R. Chung, F. Gordon, M. Curry, T. Schiano, S. Emre, K. Corey, J. Markmann, M. Hertl, J. Pomposelli, E. Pomfret, S. Florman, M. Schilsky, Teresa Broering, Robert Finberg, Gyongyi Szabo, Phillip Zamore, U. Khettry, Gregory Babcock, Donna Ambrosino, Brett Leav, Mark Leney, H. Smith, Deborah Molrine May 2013

Human Monoclonal Antibody Mbl-Hcv1 Delays Hcv Viral Rebound Following Liver Transplantation: A Randomized Controlled Study, R. Chung, F. Gordon, M. Curry, T. Schiano, S. Emre, K. Corey, J. Markmann, M. Hertl, J. Pomposelli, E. Pomfret, S. Florman, M. Schilsky, Teresa Broering, Robert Finberg, Gyongyi Szabo, Phillip Zamore, U. Khettry, Gregory Babcock, Donna Ambrosino, Brett Leav, Mark Leney, H. Smith, Deborah Molrine

Gyongyi Szabo

Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-alpha and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n=6) or placebo (n=5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated …


Inflammasomes In Liver Diseases, Gyongyi Szabo, Timea Csak Oct 2012

Inflammasomes In Liver Diseases, Gyongyi Szabo, Timea Csak

Gyongyi Szabo

Inflammation is a common element in the pathogenesis of most chronic liver diseases that lead to fibrosis and cirrhosis. Inflammation is characterized by activation of innate immune cells and production of pro-inflammatory cytokines IL-1alpha, IL-1beta, and TNFalpha. Inflammasomes are intracellular multiprotein complexes expressed in both parenchymal and non-parenchymal cells of the liver that in response to cellular danger signals activate caspase-1, and release IL-1beta and IL-18. The importance of inflammasome activation in various forms of liver diseases in relation to liver damage, steatosis, inflammation and fibrosis is discussed in this review. Elsevier B.V. All rights reserved.


Hypoxia And Hypoxia Inducible Factors: Diverse Roles In Liver Diseases, Bharath Nath, Gyongyi Szabo Oct 2012

Hypoxia And Hypoxia Inducible Factors: Diverse Roles In Liver Diseases, Bharath Nath, Gyongyi Szabo

Gyongyi Szabo

Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The hypoxia inducible factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the HIFs and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as …


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 Oct 2012

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 …


Human Monoclonal Antibody Hcv1 Effectively Prevents And Treats Hcv Infection In Chimpanzees, Trevor J. Morin, Teresa J. Broering, Brett A. Leav, Barbara M. Blair, Kirk J. Rowley, Elisabeth N. Boucher, Yang Wang, Peter S. Cheslock, Michael Knauber, David B. Olsen, Steve W. Ludmerer, Gyongyi Szabo, Robert W. Finberg, Robert H. Purcell, Robert E. Lanford, Donna M. Ambrosino, Deborah C. Molrine, Gregory J. Babcock Oct 2012

Human Monoclonal Antibody Hcv1 Effectively Prevents And Treats Hcv Infection In Chimpanzees, Trevor J. Morin, Teresa J. Broering, Brett A. Leav, Barbara M. Blair, Kirk J. Rowley, Elisabeth N. Boucher, Yang Wang, Peter S. Cheslock, Michael Knauber, David B. Olsen, Steve W. Ludmerer, Gyongyi Szabo, Robert W. Finberg, Robert H. Purcell, Robert E. Lanford, Donna M. Ambrosino, Deborah C. Molrine, Gregory J. Babcock

Gyongyi Szabo

Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and there is an urgent need to develop therapies to reduce rates of HCV infection of transplanted livers. Approved therapeutics for HCV are poorly tolerated and are of limited efficacy in this patient population. Human monoclonal antibody HCV1 recognizes a highly-conserved linear epitope of the HCV E2 envelope glycoprotein (amino acids 412-423) and neutralizes a broad range of HCV genotypes. In a chimpanzee model, a single dose of 250 mg/kg HCV1 delivered 30 minutes prior to infusion with genotype 1a H77 HCV provided complete protection from HCV infection, …


Cd81/Cd9 Tetraspanins Aid Plasmacytoid Dendritic Cells In Recognition Of Hcv-Infected Cells And Induction Of Ifnalpha, Shuye Zhang, Karen Kodys, Gregory Babcock, Gyongyi Szabo Oct 2012

Cd81/Cd9 Tetraspanins Aid Plasmacytoid Dendritic Cells In Recognition Of Hcv-Infected Cells And Induction Of Ifnalpha, Shuye Zhang, Karen Kodys, Gregory Babcock, Gyongyi Szabo

Gyongyi Szabo

Recognition of hepatitis C virus (HCV)-infected hepatocyes and interferon (IFN) induction are critical in antiviral immune response. We hypothesized that cell-cell contact between plasmacytoid dendritic cells (pDCs) and HCV-infected cells was required for IFNalpha induction via involvement of cell surface molecules. Co-culture of human peripheral blood mononuclear cells (PBMCs) with genotype 1a full length HCV genomic replicon cells (FL) or genotype 2a JFH-1 virus infected hepatoma cells (JFH-1), not with uninfected hepatoma cells (Huh7.5), induced IFNalpha production. Depletion of pDCs from PBMCs attenuated IFNalpha release and purified pDCs produced high levels of IFNalpha after co-culture with FL replicons or JFH-1 …


Il-1 Receptor Antagonist Ameliorates Inflammasome-Dependent Alcoholic Steatohepatitis In Mice, Jan Petrasek, Shashi Bala, Timea Csak, Dora Lippai, Karen Kodys, Victoria Menashy, Matthew Barrieau, So-Yun Min, Evelyn A. Kurt-Jones, Gyongyi Szabo Oct 2012

Il-1 Receptor Antagonist Ameliorates Inflammasome-Dependent Alcoholic Steatohepatitis In Mice, Jan Petrasek, Shashi Bala, Timea Csak, Dora Lippai, Karen Kodys, Victoria Menashy, Matthew Barrieau, So-Yun Min, Evelyn A. Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

Alcoholic liver disease (ALD) is characterized by steatosis and upregulation of proinflammatory cytokines, including IL-1beta. IL-1beta, type I IL-1 receptor (IL-1R1), and IL-1 receptor antagonist (IL-1Ra) are all important regulators of the IL-1 signaling complex, which plays a role in inflammation. Furthermore, IL-1beta maturation is dependent on caspase-1 (Casp-1). Using IL-1Ra-treated mice as well as 3 mouse models deficient in regulators of IL-1beta activation (Casp-1 and ASC) or signaling (IL-1R1), we found that IL-1beta signaling is required for the development of alcohol-induced liver steatosis, inflammation, and injury. Increased IL-1beta was due to upregulation of Casp-1 activity and inflammasome activation. The …