Reduced Alloreactive T-Cell Activation After Alcohol Intake Is Due To Impaired Monocyte Accessory Cell Function And Correlates With Elevated Il-10, Il-13, And Decreased Ifngamma Levels,
2010
University of Massachusetts Medical School
Reduced Alloreactive T-Cell Activation After Alcohol Intake Is Due To Impaired Monocyte Accessory Cell Function And Correlates With Elevated Il-10, Il-13, And Decreased Ifngamma Levels, Gyongyi Szabo, Pranoti Mandrekar, Angela Dolganiuc, Donna Catalano, Karen Kodys
Gyongyi Szabo
BACKGROUND: Immunosuppression associated with chronic alcohol use is characterized by reduced antigen-specific T-cell response and impaired delayed type hypersensitivity. Increasing evidence suggests in chronic alcohol consumption models that reduced antigen-specific T-cell proliferation is due to insufficient accessory cell function. Accessory cell function, a critical step in recognition of viral antigens, is reduced in chronic hepatitis C. The severity of hepatitis C is increased by alcohol consumption. Thus, we investigated the effects of alcohol consumption on accessory cell activity of monocytes in supporting alloreactive T-cell proliferation. METHODS: Alloreactive T-cell proliferation was evaluated in a one-way mixed lymphocyte reaction (MLR). Mononuclear cells …
Altered Innate Immunity In Chronic Hepatitis C Infection: Cause Or Effect,
2010
University of Massachusetts Medical School
Altered Innate Immunity In Chronic Hepatitis C Infection: Cause Or Effect, Gyongyi Szabo, Serena Chang, Angela Dolganiuc
Gyongyi Szabo
No abstract provided.
Signalling Pathways In Alcohol-Induced Liver Inflammation,
2010
University of Massachusetts Medical School
Signalling Pathways In Alcohol-Induced Liver Inflammation, Pranoti Mandrekar, Gyongyi Szabo
Gyongyi Szabo
The pathogenesis of alcoholic liver injury involves interactions of several intracellular signalling pathways in different cell types of the liver. Alcohol-induced sensitization of liver macrophages to portal endotoxin/lipopolysaccharide (LPS) is considered a hallmark of alcoholic liver disease (ALD). Intracellular mechanisms associated with LPS-induced signalling play a crucial role in the initiation and progression of alcoholic liver injury, and are being extensively explored. LPS recognition by Toll-like receptor 4 (TLR4) on macrophages and other cell types in the liver, activation of downstream signalling pathways culminating in activation of transcription factors such as NFkappaB, AP-1 leads to increased inflammatory cytokine production in …
Increased Lipopolysaccharide Sensitivity In Alcoholic Fatty Livers Is Independent Of Leptin Deficiency And Toll-Like Receptor 4 (Tlr4) Or Tlr2 Mrna Expression,
2010
University of Massachusetts Medical School
Increased Lipopolysaccharide Sensitivity In Alcoholic Fatty Livers Is Independent Of Leptin Deficiency And Toll-Like Receptor 4 (Tlr4) Or Tlr2 Mrna Expression, Laszlo Romics, Pranoti Mandrekar, Karen Kodys, Arumugam Velayudham, Yvonne Drechsler, Angela Dolganiuc, Gyongyi Szabo
Gyongyi Szabo
BACKGROUND: Both alcoholic (AFL) and nonalcoholic (NAFL) fatty livers show increased sensitivity to endotoxin-induced injury. Lipopolysaccharide (LPS) is recognized by toll-like receptor 4 (TLR4), whereas lipopeptide triggers TLR2 to induce common downstream activation of nuclear factor (NF)-kappaB and pro-inflammatory pathways that are activated in AFL and NAFL. METHODS: Serum alanine aminotransferase (ALT), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 levels; hepatic NF-kappaB activity; and expression of TLR2, TLR4, inducible nitric oxide synthase (iNOS), and heme oxygenase (HO)-1 mRNAs were investigated in lean and leptin-deficient ob/ob mice after LPS challenge in combination with acute or chronic alcohol feeding. RESULTS: Increased LPS …
Inhibitory Effect Of Monocyte Reactive Antibodies On Monocyte Chemotaxis In Systemic Lupus Erythematosus,
2010
University of Massachusetts Medical School
Inhibitory Effect Of Monocyte Reactive Antibodies On Monocyte Chemotaxis In Systemic Lupus Erythematosus, Gyula Szegedi, Katalin Lukacs, E. Bodolay, L. Gulacsi, Ildiko Sonkoly, Gyongyi Szabo, J. Szollosi
Gyongyi Szabo
Presence of different types of autoantibodies is a basic feature of systemic lupus erythematosus (SLE). Though monocytes, macrophages play an important role in cellular immunity, autoantibodies against monocytes have not been sufficiently studied. The authors used automatic fluorochromatic assay to detect monocyte reactive autoantibodies in the sera of SLE patients. Of SLE 35.5% sera showed complement-mediated monocytotoxic activity against healthy monocytes. Monocyte reactive SLE sera as well as monoclonal antibodies against human monocytes inhibited chemotaxis of control monocytes. The results suggest that monocyte reactive autoantibodies may play a role in the decreased monocyte number and defective monocyte functions observed in …
Selective Priming To Toll-Like Receptor 4 (Tlr4), Not Tlr2, Ligands By P. Acnes Involves Up-Regulation Of Md-2 In Mice,
2010
University of Massachusetts Medical School
Selective Priming To Toll-Like Receptor 4 (Tlr4), Not Tlr2, Ligands By P. Acnes Involves Up-Regulation Of Md-2 In Mice, Laszlo Romics, Angela Dolganiuc, Karen Kodys, Yvonne Drechsler, Shilpa Oak, Arumugam Velayudham, Pranoti Mandrekar, Gyongyi Szabo
Gyongyi Szabo
Lipopolysaccharide (LPS) triggers cytokine production through Toll-like receptor 4 (TLR4), which shares downstream signaling pathways with TLR2. We investigated the roles of TLR2 and TLR4 in Propionibacterium acnes (P. acnes)-primed, LPS-induced liver damage using selective TLR ligands. Stock LPS induced interleukin 8 in both TLR4- and TLR2-expressing human embryonic kidney (HEK) 293 cells. Purified LPS (TLR4 ligand) activated HEK/TLR4 cells, while peptidoglycan and lipoteichoic acid (TLR2 ligands) activated HEK/TLR2 cells, respectively. In mice, P. acnes priming resulted in increased liver messenger RNA (mRNA) and serum levels of tumor necrosis factor alpha, interleukin 12, and interferon gamma (IFN-gamma) by both stock …
Regulation Of Human Monocyte Functions By Acute Ethanol Treatment: Decreased Tumor Necrosis Factor-Alpha, Interleukin-1 Beta And Elevated Interleukin-10, And Transforming Growth Factor-Beta Production,
2010
University of Massachusetts Medical School
Regulation Of Human Monocyte Functions By Acute Ethanol Treatment: Decreased Tumor Necrosis Factor-Alpha, Interleukin-1 Beta And Elevated Interleukin-10, And Transforming Growth Factor-Beta Production, Gyongyi Szabo, Pranoti Mandrekar, Linda Girouard, Donna Catalano
Gyongyi Szabo
We and others have previously shown that even acute ethanol exposure has the capacity to modulate immune functions, particularly monocyte functions. Herein, we tested the hypothesis that acute ethanol treatment inhibits inflammatory, while increasing inhibitory cytokine production in human blood monocytes that, in turn, could contribute to the overall immune abnormalities seen after alcohol use. Our data show that in vitro treatment of blood monocytes with a physiologically relevant dose of alcohol (25 mM) results in significantly decreased induction of tumor necrosis factor-alpha (TNF alpha) and interleukin (IL)-1 beta by bacterial stimulation of either Gram-positive [staphylococcal enterotoxin B (SEB), 1 …
Monocytes, Alcohol Use, And Altered Immunity,
2010
University of Massachusetts Medical School
Monocytes, Alcohol Use, And Altered Immunity, Gyongyi Szabo
Gyongyi Szabo
The immunomodulatory capacity of acute, moderate alcohol consumption was investigated in this study in nonalcoholic volunteers after 2 ml of vodka/kg body weight of alcohol consumption. There was a significant, transient increase in interleukin-12 and interferon-gamma (IFNgamma) levels in whole blood samples collected 4 hr after alcohol consumption in response to an ex vivo bacterial challenge with lipopolysaccharide (p < 0.02). However, decreased IFNgamma levels were produced by mononuclear cells collected later after alcohol consumption (16 hr), suggesting that acute alcohol consumption has a biphasic effect on IFNgamma inducibility. Furthermore, isolated blood monocytes collected 16 hr after alcohol consumption showed significantly …
Human Monocytes, Macrophages, And Dendritic Cells: Alcohol Treatment Methods,
2010
University of Massachusetts Medical School
Human Monocytes, Macrophages, And Dendritic Cells: Alcohol Treatment Methods, Gyongyi Szabo, Pranoti Mandrekar
Gyongyi Szabo
Both acute and chronic alcohol consumption have significant immunomodulatory effects of which alterations in innate immune functions contribute to impaired antimicrobial defense and inflammatory responses. Blood monocytes, macrophages, and dendritic cells play a central role in innate immune recognition as these cells recognize pathogens, respond with inflammatory cytokine production, and induce antigen-specific T-lymphocyte activation. All of these innate immune cell functions are affected in humans by alcohol intake. Here, we summarize the different effects of acute and chronic alcohol on monocyte, macrophage, and dendritic cell functions in humans and describe methods for separation and functional evaluation of these cell types.
Antigen-Presenting Cells Under The Influence Of Alcohol,
2010
University of California
Antigen-Presenting Cells Under The Influence Of Alcohol, Audrey Lau, Gyongyi Szabo, Angus Thomson
Gyongyi Szabo
The negative influence of alcohol (ethanol) and its metabolites on innate and adaptive immunity is well-recognized. Much attention has recently been focused on the impact of acute and chronic alcohol exposure on antigen-presenting cells (APC). In particular, insights have been gained into how the properties of human blood monocytes and rodent macrophages are influenced by alcohol in vitro and in vivo. Here, we review the impact of alcohol on various aspects of APC function and the underlying mechanisms, including its effects on intracellular signaling events. We also discuss new information regarding the influence of alcohol on various APC populations in …
Alcohol-Induced Modulation Of Signaling Pathways In Liver Parenchymal And Nonparenchymal Cells: Implications For Immunity,
2010
University of Massachusetts Medical School
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, …
Polymorphonuclear Functions In Patients With Mixed Connective Tissue Disease,
2010
University of Massachusetts Medical School
Polymorphonuclear Functions In Patients With Mixed Connective Tissue Disease, E. Bodolay, Katalin Lukacs, G. Frendl, Gyongyi Szabo, G. Arato, Gyula Szegedi
Gyongyi Szabo
Polymorphonuclear leukocytes (PMNs) from 29 patients with mixed connective tissue disease (MCTD) were studied "in vitro" for their phagocytic and chemotactic function as well as for granulocyte alkaline phosphatase (GAP) activity. Fc-receptor expression detected by EA-rosette formation was comparable to the control. Yeast-phagocytosis, C3b-receptor mediated phagocytosis and chemotaxis of PMNs, however, significantly decreased in MCTD. At the same time, photometric measure of alkaline phosphatase activity indicated a nearly two fold increase in PMNs from patients with MCTD. Although no correlation was found between PMN functions and the activity of the disease, PMN disorders may play a role in pathogenesis of …
Acute Alcohol Inhibits The Induction Of Nuclear Regulatory Factor Kappa B Activation Through Cd14/Toll-Like Receptor 4, Interleukin-1, And Tumor Necrosis Factor Receptors: A Common Mechanism Independent Of Inhibitory Kappa B Alpha Degradation,
2010
University of Massachusetts Medical School
Acute Alcohol Inhibits The Induction Of Nuclear Regulatory Factor Kappa B Activation Through Cd14/Toll-Like Receptor 4, Interleukin-1, And Tumor Necrosis Factor Receptors: A Common Mechanism Independent Of Inhibitory Kappa B Alpha Degradation, Pranoti Mandrekar, Angela Dolganiuc, Gary Bellerose, Karen Kodys, Laszlo Romics, Rabia Nizamani, Gyongyi Szabo
Gyongyi Szabo
BACKGROUND: Nuclear translocation and DNA binding of the nuclear factor kappaB (NF-kappaB) is an early event in inflammatory cell activation in response to stimulation with bacterial components or cytokines. Cell activation via different receptors culminates in a common pathway leading to NF-kappaB activation and proinflammatory cytokine induction. We have previously shown that acute alcohol inhibits NF-kappaB activation by lipopolysaccharide (LPS) in human monocytes. Here we investigated whether acute alcohol treatment of human monocytes also inhibits NF-kappaB when induced through activation of the interleukin (IL)-1 or tumor necrosis factor (TNF) receptors. METHODS: Human peripheral blood monocytes were treated with LPS, TNFalpha, …
Monocyte Functions In Patients With Mixed Connective Tissue Disease,
2010
University of Massachusetts Medical School
Monocyte Functions In Patients With Mixed Connective Tissue Disease, E. Bodolay, Katalin Lukacs, Gyongyi Szabo, G. Frendl, T. Ben, Gyula Szegedi
Gyongyi Szabo
The authors investigated the number and functions of peripheral blood monocytes in patients with mixed connective tissue disease. Moderate monocytopenia was detected in the active stage of the disease. There was a close correlation between the sensitized sheep red blood cell binding capacity of monocytes and the elevated levels of circulating immune complexes. The yeast phagocytosis of monocytes and the chemotactic activity were normal in patients with mixed connective tissue disease. C3b receptor mediated phagocytosis of monocytes decreased in the active and inactive stages of the disease. This study suggests that the decreased function of C3b receptors of monocytes is …
Human Macrophages Degrade Tryptophan Upon Induction By Interferon-Gamma,
2010
University of Massachusetts Medical School
Human Macrophages Degrade Tryptophan Upon Induction By Interferon-Gamma, Ernst Werner, Gabriele Bitterlich, Dietmar Fuchs, Arno Hausen, Gilbert Reibnegger, Gyongyi Szabo, Manfred Dierich, Helmut Wachter
Gyongyi Szabo
Human peripheral blood mononuclear cells, monocytes-macrophages and T-cells were stimulated with human recombinant interferon-gamma, interferon-alpha and phytohemagglutinin. The culture supernatants were analyzed for tryptophan, kynurenine, 3-hydroxyanthranilic acid, anthranilic acid and neopterin by high performance liquid chromatography. Tryptophan was decreased and the four other compounds were increased in supernatants of peripheral blood mononuclear cells activated by interferon-gamma (250 U/ml), interferon-alpha (10.000 U/ml) and phytohemagglutinin (1 microgram/ml). After splitting of peripheral blood mononuclear cells by adherence, the monocytes and macrophages but not the T-cells degraded tryptophan upon stimulation by interferon-gamma in a dose dependent manner. Supernatants of phytohemagglutinin stimulated but not of …
New Insights Into The The Molecular Mechanisms Of Alcoholic Hepatitis: A Potential Role For Nf-Kappab Activation,
2010
University of Massachusetts Medical School
New Insights Into The The Molecular Mechanisms Of Alcoholic Hepatitis: A Potential Role For Nf-Kappab Activation, Gyongyi Szabo
Gyongyi Szabo
No abstract provided.
Vsl#3 Probiotic Treatment Attenuates Fibrosis Without Changes In Steatohepatitis In A Diet-Induced Nonalcoholic Steatohepatitis Model In Mice,
2010
University of Massachusetts Medical School
Vsl#3 Probiotic Treatment Attenuates Fibrosis Without Changes In Steatohepatitis In A Diet-Induced Nonalcoholic Steatohepatitis Model In Mice, Arumugam Velayudham, Angela Dolganiuc, Michael Ellis, Jan Petrasek, Karen Kodys, Pranoti Mandrekar, Gyongyi Szabo
Gyongyi Szabo
Nonalcoholic fatty liver disease (NAFLD) and its advanced stage, nonalcoholic steatohepatitis (NASH), are the most common causes of chronic liver disease in the United States. NASH features the metabolic syndrome, inflammation, and fibrosis. Probiotics exhibit immunoregulatory and anti-inflammatory activity. We tested the hypothesis that probiotic VSL#3 may ameliorate the methionine-choline-deficient (MCD) diet-induced mouse model of NASH. MCD diet resulted in NASH in C57BL/6 mice compared to methionine-choline-supplemented (MCS) diet feeding evidenced by liver steatosis, increased triglycerides, inflammatory cell accumulation, increased tumor necrosis factor alpha levels, and fibrosis. VSL#3 failed to prevent MCD-induced liver steatosis or inflammation. MCD diet, even in …
Regulation Of Monocyte Interleukin-12 Production By Acute Alcohol: A Role For Inhibition By Interleukin-10,
2010
University of Massachusetts Medical School
Regulation Of Monocyte Interleukin-12 Production By Acute Alcohol: A Role For Inhibition By Interleukin-10, Linda Girouard, Pranoti Mandrekar, Donna Catalano, Gyongyi Szabo
Gyongyi Szabo
Acute ethanol treatment results in decreased antigen presentation capacity (Th1-type immunity) and elevated interleukin IL-10 (Th2 cytokine) production in human monocytes. Monocytes can contribute to both Th1 (IL-12) and Th2 (IL-10) immune responses via production of IL-12 and IL-10, respectively. Thus, we tested the hypothesis that acute alcohol treatment might affect Th1/Th2 immune balance by altering monocyte production of IL-12 and IL-10. Neither acute ethanol treatment alone (25 to 100 mM) nor its combination with a bacterial challenge Staphylococcal enterotoxin B (SEB) induced IL-12 production in isolated blood monocytes. In contrast, the same physiological alcohol concentrations increased monocyte IL-10 levels, …
Hepatitis C Core And Nonstructural 3 Proteins Trigger Toll-Like Receptor 2-Mediated Pathways And Inflammatory Activation,
2010
University of Massachusetts Medical School
Hepatitis C Core And Nonstructural 3 Proteins Trigger Toll-Like Receptor 2-Mediated Pathways And Inflammatory Activation, Angela Dolganiuc, Shilpa Oak, Karen Kodys, Douglas Golenbock, Robert Finberg, Evelyn Kurt-Jones, Gyongyi Szabo
Gyongyi Szabo
BACKGROUND AND AIMS: Recent evidence suggests that toll-like receptors (TLRs) recognize certain viruses. We reported that hepatitis C virus (HCV) core and nonstructural 3 (NS3) proteins activate inflammatory pathways in monocytes. The aim of this study was to investigate the role of TLRs in innate immune cell activation by core and NS3 proteins. METHODS: Human monocytes, human embryonic kidney cells transfected with TLR2, and peritoneal macrophages from TLR2, MyD88 knockout, and wild-type mice were studied to determine intracellular signaling and proinflammatory cytokine induction by HCV proteins. RESULTS: HCV core and NS3 proteins triggered inflammatory cell activation via the pattern recognition …
Subversion Of Plasmacytoid And Myeloid Dendritic Cell Functions In Chronic Hcv Infection,
2010
University of Massachusetts Medical School
Subversion Of Plasmacytoid And Myeloid Dendritic Cell Functions In Chronic Hcv Infection, Gyongyi Szabo, Angela Dolganiuc
Gyongyi Szabo
Insufficient elimination of the hepatitis C virus (HCV) during acute infection results in chronic disease in the majority of patients due to weak virus-specific immune responses. Dendritic cells (DC) play a central role in recognition of HCV and in induction of innate and adaptive immune responses. In this study, we evaluated the frequency and functions of plasmacytoid dendritic cells (PDC) and myeloid dendritic cells (MDC) in patients with chronic HCV infection. We found that both the numbers and IFNalpha production capacity of blood PDC were significantly reduced in patients with chronic HCV infection compared to normal controls. While the frequency …
