Diseases Commons^™

Reduction In Hepatic Inflammation Is Associated With Less Fibrosis Progression And Fewer Clinical Outcomes In Advanced Hepatitis C, Chihiro Morishima, Mitchell Shiffman, Jules Dienstag, Karen Lindsay, Gyongyi Szabo, Gregory Everson, Anna Lok, Adrian Di Bisceglie, Marc Ghany, Deepa Naishadham, Timothy Morgan, Elizabeth Wright

Gyongyi Szabo

OBJECTIVES:During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation. METHODS:Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological …

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 …

Hepatocyte-Specific Hypoxia-Inducible Factor-1alpha Is A Determinant Of Lipid Accumulation And Liver Injury In Alcohol-Induced Steatosis In Mice, Bharath Nath, Ivan Levin, Timea Csak, Jan Petrasek, Christian Mueller, Karen Kodys, Donna Catalano, Pranoti Mandrekar, Gyongyi Szabo

Gyongyi Szabo

Chronic alcohol causes hepatic steatosis and liver hypoxia. Hypoxia-regulated hypoxia-inducible factor 1-alpha, (HIF-1alpha) may regulate liporegulatory genes, but the relationship of HIF-1 to steatosis remains unknown. We investigated HIF-1alpha in alcohol-induced hepatic lipid accumulation. Alcohol administration resulted in steatosis, increased liver triglyceride levels, and increased serum alanine aminotransferase (ALT) levels, suggesting liver injury in wild-type (WT) mice. There was increased hepatic HIF-1alpha messenger RNA (mRNA), protein, and DNA-binding activity in alcohol-fed mice compared with controls. Mice engineered with hepatocyte-specific HIF-1 activation (HIF1dPA) had increased HIF-1alpha mRNA, protein, and DNA-binding activity, and alcohol feeding in HIF1dPA mice increased hepatomegaly and hepatic …

Induction Of Bcl-3 By Acute Binge Alcohol Results In Toll-Like Receptor 4/Lps Tolerance, Shashi Bala, Alexander Tang, Donna Catalano, Jan Petrasek, Odette Taha, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

Acute alcohol binge results in immunosuppression and impaired production of proinflammatory cytokines, including TNF-alpha. TNF-alpha production is induced by LPS, a TLR4 ligand, and is tightly regulated at various levels of the signaling cascade, including the NF-kappaB transcription factor. Here, we hypothesized that acute alcohol induces TLR4/LPS tolerance via Bcl-3, a nuclear protein and member of the NF-kappaB family. We found that acute alcohol pretreatment resulted in the same attenuating effect as LPS pretreatment on TLR4-induced TNF-alpha production in human monocytes and murine RAW 264.7 macrophages. Acute alcohol-induced Bcl-3 expression and IP studies revealed increased association of Bcl-3 with NF-kappaB …

Novel Developmental Biology-Based Protocol Of Embryonic Stem Cell Differentiation To Morphologically Sound And Functional Yet Immature Hepatocytes, Terence Bukong, Tracie Lo, Gyongyi Szabo, Angela Dolganiuc

Gyongyi Szabo

BACKGROUND/AIMS: Liver diseases are common in the United States and often require liver transplantation; however, donated organs are limited and thus alternative sources for liver cells are in high demand. Embryonic stem cells (ESC) can provide a continuous and readily available source of liver cells. ESC differentiation to liver cells is yet to be fully understood and comprehensive differentiation protocols are yet to be defined. Here, we aimed to achieve human (h)ESC differentiation into mature hepatocytes using defined recombinant differentiation factors and metabolites. METHODS: Embryonic stem cell H1 line was sub-cultured on feeder layer. We induced hESCs into endodermal differentiation …

Circulating Micrornas In Exosomes Indicate Hepatocyte Injury And Inflammation In Alcoholic, Drug-Induced, And Inflammatory Liver Diseases, Shashi Bala, Jan Petrasek, Shiv Mundkur, Donna Catalano, Ivan Levin, Jeanine Ward, Hawau Alao, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

MicroRNAs are fine tuners of diverse biological responses and are expressed in various cell types of the liver. Here we hypothesized that circulating microRNAs (miRNAs) may serve as biomarkers of liver damage and inflammation. We studied miRNA-122, which is abundant in hepatocytes, and miR-155, -146a, and -125b, which regulate inflammation in immune cells in mouse models of alcoholic liver disease (ALD), drug (acetaminophen, APAP)-induced liver injury (DILI), and Toll-like receptor (TLR) 9+4 ligand-induced inflammatory cell-mediated liver damage. We found that serum/plasma miR-122 correlated with alanine aminotransferase (ALT) increases in the liver damage caused by alcohol, APAP, and TLR9 (CpG)+4 (LPS) …

Fatty Acid And Endotoxin Activate Inflammasomes In Mouse Hepatocytes That Release Danger Signals To Stimulate Immune Cells, Timea Csak, Michal Ganz, Justin Pespisa, Karen Kodys, Angela Dolganiuc, Gyongyi Szabo

Gyongyi Szabo

The pathogenesis of nonalcoholic steatohepatitis (NASH) and inflammasome activation involves sequential hits. The inflammasome, which cleaves pro-interleukin-1beta (pro-IL-1beta) into secreted IL-1beta, is induced by endogenous and exogenous danger signals. Lipopolysaccharide (LPS), a toll-like receptor 4 ligand, plays a role in NASH and also activates the inflammasome. In this study, we hypothesized that the inflammasome is activated in NASH by multiple hits involving endogenous and exogenous danger signals. Using mouse models of methionine choline-deficient (MCD) diet-induced NASH and high-fat diet-induced NASH, we found up-regulation of the inflammasome [including NACHT, LRR, and PYD domains-containing protein 3 (NALP3; cryopyrin), apoptosis-associated speck-like CARD-domain containing …

A Prospective Study Of The Rate Of Progression In Compensated, Histologically Advanced Chronic Hepatitis C, Jules Dienstag, Marc Ghany, Timothy Morgan, Adrian Di Bisceglie, Herbert Bonkovsky, Hae-Young Kim, Leonard Seeff, Gyongyi Szabo, Elizabeth Wright, Richard Sterling, Gregory Everson, Karen Lindsay, William Lee, Anna Lok, Chihiro Morishima, Anne Stoddard, James Everhart

Gyongyi Szabo

The incidence of liver disease progression among subjects with histologically advanced but compensated chronic hepatitis C is incomplete. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial was a randomized study of 3.5 years of maintenance peginterferon treatment on liver disease progression among patients who had not cleared virus on peginterferon and ribavirin therapy. Patients were followed subsequently off therapy. Because maintenance peginterferon treatment did not alter liver disease progression, we analyzed treated and control patients together. Among 1,050 subjects (60% advanced fibrosis, 40% cirrhosis), we determined the rate of progression to cirrhosis over 4 years and of clinical outcomes …

Dibutyryl-Camp Modulation Of Receptor Expression And Antigen Presentation Capacity In Monocyte Subpopulations, Gyongyi Szabo, Karen Kodys, Carol Miller-Graziano

Gyongyi Szabo

Monocyte phenotype heterogeneity is often associated with functional differences between the distinguished Mphi subpopulations. We have previously demonstrated that the Mphi subpopulation separated and stimulated by rosetting Mphi via the Type I Fc gamma R (CD64) are poor antigen presenting cells but can be induced to greater production of TNF alpha, IL-6 and PGE2 than the Fc gamma RI- Mphi population. Here we demonstrate that the Fc gamma RI- Mphi represent the major antigen presenting Mphi population and that APC capacity of the FcRI- Mphi can be further increased by elevating intracellular cAMP levels. Treatment of the Fc gamma RI+ …

Effects Of Immune Complexes From Sle Patients On Human Monocyte Locomotion And Fc Receptor Function, Katalin Lukacs, Maria Kavai, Aniko Banyai, Ildiko Sonkoly, Eva Vegh, Gyongyi Szabo, Gyula Szegedi

Gyongyi Szabo

The effect of immune complexes (IC) isolated from systemic lupus erythematosus (SLE) sera with polyethylene glycol and gel filtration on the chemotaxis and Fc receptor function of healthy monocytes was examined. Even at a low protein concentration (1 microgram/ml = 1 mg/l) ICs inhibit monocyte chemotaxis. ICs from patients with SLE nephritis are more inhibitory than ICs from patients without renal disease. The inhibitory effects of ICs on monocyte chemotaxis and Fc receptor activity are similar, suggesting a relationship between the chemotactic and Fc receptor function of monocytes. Analysis of the ICs by enzyme-linked immunoassay showed no correlation between the …

Regulatory Potential Of Ethanol And Retinoic Acid On Human Monocyte Functions, Gyongyi Szabo, Maria Puppolo, Bikash Verma, Donna Catalano

Gyongyi Szabo

Retinoic acid (RA), a metabolic product of vitamin A, has been shown to affect a variety of immune functions, including monocytes. Monocyte functions and mediator production are also modulated by ethanol exposure. This study demonstrates that therapeutic doses of RA (0.1-10 microM) significantly increase transforming growth factor-beta (TGF beta) production both in THP-1, human myelomonocytic cells, and in human peripheral blood monocytes. We have previously reported TGF beta induction by ethanol in human M theta. Combination of RA stimulation with acute in vitro ethanol treatment, however, resulted in significantly lower M theta TGF beta production than TGF beta levels induced …

Consequences Of Alcohol Consumption On Host Defence, Gyongyi Szabo

Gyongyi Szabo

This communication reviews recent literature and summarizes current views on the immunomodulatory effects of acute and chronic alcohol consumption. Chronic and even acute, moderate alcohol use can increase host susceptibility to infections caused by bacterial and viral pathogens. Impaired host defence after alcohol exposure appears to be linked to a combination of decreased inflammatory response, altered cytokine production, and abnormal reactive oxygen intermediate generation. Furthermore, cellular immunity, particularly antigen-specific immune response, is impaired by both acute and chronic alcohol use. Although T lymphocyte functions can be directly affected by ethanol, decreased antigen presenting cell function appears to be a key …

Acute Alcohol Activates Stat3, Ap-1, And Sp-1 Transcription Factors Via The Family Of Src Kinases To Promote Il-10 Production In Human Monocytes, Oxana Norkina, Angela Dolganiuc, Taryn Shapiro, Karen Kodys, Pranoti Mandrekar, Gyongyi Szabo

Gyongyi Szabo

Alcohol consumption is associated with an imbalance in pro- and anti-inflammatory cytokines and immunosuppression, partially as a result of enhanced IL-10 production. The mechanisms of IL-10 induction by alcohol remain poorly understood. We identified that increased IL-10 production in human monocytes after acute in vivo alcohol consumption or in vitro alcohol treatment was associated with increased STAT3 activation. Alcohol alone induced and in combination with LPS augmented STAT3 phosphorylation at tyrosine 705 (tyr705) and serine 727 (ser727) residues and increased STAT3 binding to DNA. Upstream, alcohol activated the Src kinases, as indicated by an increase in phosphorylated and a decrease …

Alcohol's Contribution To Compromised Immunity, Gyongyi Szabo

Gyongyi Szabo

Alcoholics frequently suffer from infectious diseases and have increased rates of some cancers, indicating that alcohol impairs the immune system, which protects the body against this type of damage. Alcohol interferes with the functions of many of the cells and molecules that are part of the immune system. For example, alcohol inhibits the functions of the cells that ingest and destroy invading microorganisms (i.e., neutrophils, monocytes, and macrophages). Both acute and chronic alcohol exposure also alter the production of signaling molecules that help coordinate the immune response (i.e., cytokines). Finally, alcohol adversely affects the functions of the cells that mediate …

Mechanisms Of Altered Monocyte Prostaglandin E2 Production In Severely Injured Patients, Carol Miller-Graziano, Mitchell Fink, Jia-Yan Wu, Gyongyi Szabo, Karen Kodys

Gyongyi Szabo

Monocytes from immunosuppressed trauma (11 patients) and burn (12 patients) patients stimulated with muramyl dipeptide, a potent prostaglandin E2 (PGE2) secretagogue, showed twofold greater PGE2 production compared with normal controls or immunocompetent patients. Monocyte plasminogen activator production was markedly depressed and inversely correlated to patients' monocyte hyper PGE2 production. Levels of the PGE2-producing monocyte subset (selected as high-affinity Fc+ receptors) were progressively elevated after injury in immunosuppressed patients, reaching 65% to 80% of the total monocyte population (39% for normal controls). Although early T-suppressor (Ts) lymphocytes did not augment monocyte PGE2 secretion, Ts lymphocytes that appeared late (greater than 12 …

Acute Alcohol Consumption Attenuates Interleukin-8 (Il-8) And Monocyte Chemoattractant Peptide-1 (Mcp-1) Induction In Response To Ex Vivo Stimulation, Gyongyi Szabo, Sangeeta Chavan, Pranoti Mandrekar, Donna Catalano

Gyongyi Szabo

No abstract provided.

A Recent Perspective On Alcohol, Immunity, And Host Defense, Gyongyi Szabo, Pranoti Mandrekar

Gyongyi Szabo

BACKGROUND: Multiple line of clinical and experimental evidence demonstrates that both acute, moderate, and chronic, excessive alcohol use result in various abnormalities in the functions of the immune system.

METHODS: Medline and PubMed databases were used to identify published reports with particular interest in the period of 2000-2008 in the subject of alcohol use, infection, inflammation, innate, and adaptive immunity.

RESULTS: This review article summarizes recent findings relevant to acute or chronic alcohol use-induced immunomodulation and its consequences on host defense against microbial pathogens and tissue injury. Studies with in vivo and in vitro alcohol administration are both discussed. The …

Acute Ethanol Consumption Synergizes With Trauma To Increase Monocyte Tumor Necrosis Factor Alpha Production Late Postinjury, Gyongyi Szabo, Pranoti Mandrekar, Bikash Verma, Ann Isaac, Donna Catalano

Gyongyi Szabo

The hypothesis that acute ethanol uptake plus trauma can synergize to increase immunosuppression was tested. We found that, unlike non-alcohol-exposed patients, patients with acute alcohol use prior to trauma have a transient decrease in monocyte tumor necrosis factor alpha (TNF alpha) production during the very early postinjury (0-3 days) period. However, TNF alpha production by these alcohol-exposed patients' monocytes (M0) became hyperelevated late postinjury (> 9 days). Consequently, these massively elevated M0 TNF alpha levels can contribute to posttrauma immunosuppression after acute alcohol use. We also demonstrate that normal monocyte activation with the superantigen, Staphylococcus enterotoxin B (SEB), results in …

The Emerging Role Of Toll-Like Receptor Pathways In Surgical Diseases, Laszlo Romics, Gyongyi Szabo, John Calvin Coffey, Jiang Huai Wang, Henry Paul Redmond

Gyongyi Szabo

OBJECTIVE: To outline the emerging significance of Toll-like receptor (TLR) signaling pathways in surgical diseases. DATA

SOURCES: A systematic review of the literature was undertaken by searching the MEDLINE database for the period 1966 to 2005 without language restriction.

STUDY SELECTION: Original or review articles that described experimental data on the activation of TLR signaling pathways in surgically relevant diseases were selected for inclusion in this review.

DATA EXTRACTION: Data were obtained from peer-reviewed articles and references.

DATA SYNTHESIS: The role of TLRs in the recognition of pathogens renders them a key figure in the activation of both innate and …

Human Monocyte Il-10 Production Is Increased By Acute Ethanol Treatment, Pranoti Mandrekar, Donna Catalano, Linda Girouard, Gyongyi Szabo

Gyongyi Szabo

Immune alterations after acute ethanol treatment are characterized by abnormal monocyte mediator production and antigen presentation capacity. Here, we tested the hypothesis that some of the regulatory effects of ethanol on monocyte functions are mediated by elevated M phi IL-10 production. Physiologically relevant in vitro doses of ethanol (25-100 mM) resulted in significantly increased IL-10 secretion by normal blood monocytes after 18 h stimulation. We found that monocyte IL-10 production induced by either ethanol or LPS increased at 10 h, maximized at 18 h and decreased by 40 h post-stimulation. Furthermore, ethanol significantly augmented LPS-induced monocyte IL-10 secretion at 18 …

Down-Regulation Of Tumor Necrosis Factor Alpha Activity By Acute Ethanol Treatment In Human Peripheral Blood Monocytes, Bikash Verma, Miklos Fogarasi, Gyongyi Szabo

Gyongyi Szabo

As the most commonly used drug that can modulate both metabolic and immune pathways, ethanol is evaluated in this report as a regulator of tumor necrosis factor alpha (TNF alpha) production in human peripheral blood monocytes (M phi) in combination with a variety of stimuli. While acute ethanol treatment did not induce TNF alpha in M phi, it was a potent down-regulator of M phi TNF alpha production whether induced by the combination of interferon-gamma plus muramyl dipeptide (MDP) (P < 0.001), lipopolysaccharide (LPS) alone (P < 0.01), or interferon-gamma plus LPS. Down-regulation of M phi TNF alpha by ethanol was dose dependent and statistically significant in the biologically relevant, 25-150 mM, ethanol concentration range. We also demonstrate that these ethanol concentrations did not affect M phi viability. TNF alpha down-regulation by ethanol was most effective when ethanol was administered 4 hr prior to MDP stimulation; however, it was also effective--though to a lesser extent--if it was added at the time of MDP stimulation. Furthermore, ethanol also down-regulated TNF alpha production of the in vivo preactivated M phi of trauma patients, which produce hyperelevated levels of TNF alpha. We have previously shown that the majority of posttrauma elevated M phi TNF alpha is produced by the M phi subpopulation expressing high-affinity type I Fc gamma receptors (Fc gamma RI). When the Fc gamma RI cross-linking-stimulated M phi subpopulation was treated with acute ethanol, TNF alpha production was suppressed again both in in vivo preactivated M phi of trauma patients and in M phi of normal controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Alcohol Consumption Inhibits Accessory Cell Function Of Monocytes And Dendritic Cells, Gyongyi Szabo, Donna Catalano, Bernadette White, Pranoti Mandrekar

Gyongyi Szabo

BACKGROUND: Alcohol affects both innate and acquired immune responses. Chronic alcoholics have reduced delayed-type hypersensitivity response and increased susceptibility to infections. In contrast, recent studies suggest that acute, moderate alcohol consumption has protective effects on mortality. Monocytes and dendritic cells (DC) play a central role in coordination of innate and adaptive immune responses and are pivotal in activation of T lymphocytes in an antigen-specific manner. In this study, we investigated the effects of acute, moderate alcohol consumption on antigen presenting cell function of blood monocytes and monocyte-derived myeloid dendritic cells. METHODS: Accessory cell function of human blood monocytes was tested …

Moderate Alcohol Intake In Humans Attenuates Monocyte Inflammatory Responses: Inhibition Of Nuclear Regulatory Factor Kappa B And Induction Of Interleukin 10, Pranoti Mandrekar, Donna Catalano, Bernadette White, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND: In contrast to the deleterious effects of chronic excessive alcohol consumption on the liver and cardiovascular system, modest alcohol intake, such as 1 to 2 drinks per day, has benefits on cardiovascular mortality. Little is known about the length of time or the amounts of alcohol consumed that may cause alterations in inflammatory cells such as monocytes that are crucial to atherosclerotic vascular disease. Here, we determine in vivo effects of acute alcohol consumption on inflammatory cytokine production and nuclear regulatory factor kappaB (NF-kappaB) binding in human monocytes. METHODS: Human blood monocytes were isolated by plastic adherence before and …