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Modulation Of Immunity And Viral-Host Interactions By Alcohol, Geoffrey Thiele, Gyongyi Szabo, Elizabeth Kovacs, Abraham Bautista, Laura Sosa, Thomas Jerrells

Gyongyi Szabo

This manuscript represents the proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada. The organizers/chairs were Gyongyi Szabo and Geoffrey M. Thiele. The presentations were (1) Introduction, by Gyongyi Szabo; (2) Chemokine dysregulation after acute ethanol exposure, by Elizabeth J. Kovacs; (3) Chemokine production and innate immunity in the livers of simian immunodeficiency virus-infected Macaca mulatta following chronic alcohol administration, by Abraham P. Bautista; (4) Influence of ethanol consumption on the severity and progression of hepatitis associated with cytomegalovirus infection, by Laura Sosa and Thomas R. Jerrells; (5) Scavenger receptor involvement in the immune response to the …

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.

Rsa 2004: Combined Basic Research Satellite Symposium - Session Three: Alcohol And Mitochondrial Metabolism: At The Crossroads Of Life And Death, Gyongyi Szabo, Jan Hoek, Victor Darley-Usmar, Gyorgy Hajnoczky, Thomas Knudsen, Daria Mochly-Rosen, Samir Zakhari

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, CA. One of the sessions "Alcohol and mitochondrial metabolism: At the crossroads of life and death" featured five speakers and was chaired by Drs. Jan Hoek and Sam Zakhari. The presentations were 1) Introduction: Alcohol and cellular energy metabolism by Jan Hoek, 2) Ethanol-dependent dysfunction of mitochondrial energy metabolism: the role of NO by Victor Darley-Usmar, 3) Ethanol and apoptosis in the heart by Gyorgy Hajnoczky, 4) Alcohol and mitochondrial biogenesis in development by Thomas Knudsen, and …

Aberrations In Post-Trauma Monocyte (Mo) Subpopulation: Role In Septic Shock Syndrome, Carol Miller-Graziano, Gyongyi Szabo, Karen Kodys, Katherine Griffey

Gyongyi Szabo

Appearance of increased proportions of monocytes bearing the 72kd(FcRI) receptor for IgG correlated to aberrant monocyte (MO) functions, depressed immune functions, and poor clinical outcome. The trauma patients' FcRI+ MO subpopulation produced the majority of their elevated IL-6, TNF alpha, TGF beta, and PGE2. IgG stimulation of patients' MO through FcRI not only stimulated TNF alpha, IL-6, and PGE2 levels, but also greatly augmented the levels of these monokines produced after subsequent bacterial challenge. Post-trauma increased IL-6 levels can lead to polyclonal B-cell activation and high levels of circulating, nonspecific IgG as seen in trauma patients. This nonspecific IgG triggers …

Intervention At The Level Of The Neuroendocrine-Immune Axis And Postoperative Pneumonia Rate In Long-Term Alcoholics, Claudia Spies, Verena Eggers, Gyongyi Szabo, Alexandra Lau, Vera Von Dossow, Helge Schoenfeld, Hilke Althoff, Katrin Hegenscheid, Birgit Bohm, Torsten Schroeder, Sebastian Pfeiffer, Sabine Ziemer, Christian Paschen, Martin Klein, Christian Marks, Peter Miller, Michael Sander, Klaus-D. Wernecke, Evelin Achterberg, Udo Kaisers, Hans-Dieter Volk

Gyongyi Szabo

RATIONALE: Postoperative pneumonia is three to four times more frequent in patients with alcohol use disorders followed by prolonged intensive care unit (ICU) stay. Long-term alcohol use leads to an altered perioperative hypothalamus-pituitary-adrenal (HPA) axis and immunity. OBJECTIVES: The aim of this study was to evaluate HPA intervention with low-dose ethanol, morphine, or ketoconazole on the neuroendocrine-immune axis and development of postoperative pneumonia in long-term alcoholic patients. METHODS: In this randomized, double-blind controlled study, 122 consecutive patients undergoing elective surgery for aerodigestive tract cancer were included. Long-term alcohol use was defined as consuming at least 60 g of ethanol daily …

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+ …

The "Health" And Future Of The Physician-Scientist In Hepatology, Gyongyi Szabo

Gyongyi Szabo

No abstract provided.

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 …

Role Of Elevated Monocyte Transforming Growth Factor Beta (Tgf Beta) Production In Posttrauma Immunosuppression, Carol Miller-Graziano, Gyongyi Szabo, Katherine Griffey, Bela Mehta, Karen Kodys, Donna Catalano

Gyongyi Szabo

We previously reported that increased production of prostaglandin E2 by monocytes is a pivotal mechanism in posttrauma immunopathology. Here we characterize monocyte levels of transforming growth factor beta and examine the effects of elevated transforming growth factor beta on prostaglandin E2 release by patients' monocytes. Trauma patients' and normals' monocyte supernates (+/- stimulation with muramyl dipeptide) were acid treated and assayed for transforming growth factor beta using the mink lung-cell bioassay. Alternatively, human transforming growth factor beta was added to patients' and normals' monocytes and prostaglandin E2 production assayed. Significantly elevated transforming growth factor beta levels (median = 181.7 pmol/10(6) …

Tacrolimus And Cyclosporine A Inhibit Allostimulatory Capacity And Cytokine Production Of Human Myeloid Dendritic Cells, Gyongyi Szabo, C. Gavala, Pranoti Mandrekar

Gyongyi Szabo

Myeloid dendritic cells (DCs) are pivotal in the recognition of alloantigens and, therefore, in the induction of allograft rejection. Induction of alloreactive T cell proliferation by myeloid DCs depends on the maturation of DCs, the expression of costimulatory molecules, and the cytokine environment. This study investigated the effects of tacrolimus and cyclosporine A (CsA) on DC maturation and allostimulatory capacity. Myeloid DCs were propagated from normal blood monocytes with interleukin (IL) 4 and GM-CSF for 7 days in the presence or absence of tacrolimus (FK506; 10 nM) or CsA (1 microg/mL). Exposure of DCs during maturation to tacrolimus or CsA …

Cytokines And Alcohol, Fulton Crews, Rabih Bechara, Lou Ann Brown, David Guidot, Pranoti Mandrekar, Shilpa Oak, Liya Qin, Gyongyi Szabo, Michael Wheeler, Jian Zou

Gyongyi Szabo

Cytokines are multifunctional proteins that play a critical role in cellular communication and activation. Cytokines have been classified as being proinflammatory (T helper 1, Th1) or anti-inflammatory (T helper 2, Th2) depending on their effects on the immune system. However, cytokines impact a variety of tissues in a complex manner that regulates inflammation, cell death, and cell proliferation and migration as well as healing mechanisms. Ethanol (alcohol) is known to alter cytokine levels in a variety of tissues including plasma, lung, liver, and brain. Studies on human monocyte responses to pathogens reveal ethanol disruption of cytokine production depending upon the …

Effect Of Ethanol On Inflammatory Responses. Implications For Pancreatitis, Gyongyi Szabo, Pranoti Mandrekar, Shilpa Oak, Julia Mayerle

Gyongyi Szabo

BACKGROUND/AIMS: Alcohol use alters inflammatory cell responses. While alcohol has direct effects on pancreatic acinar cells, activation of inflammatory cells is a major component of the pathology of alcoholic pancreatitis.

METHODS: The effects of acute or chronic alcohol exposure were evaluated in human monocytes on the production of TNFalpha or IL-10 production, pro-inflammatory gene and nuclear factor-kappaB (NF-kappaB) activation.

RESULTS: Moderate, acute alcohol consumption or equivalent doses of alcohol in vitro had anti-inflammatory effects on monocyte activation via inhibition of pro-inflammatory genes and NF-kappaB activation, inhibition of TNFalpha production and augmentation of the anti-inflammatory cytokine, IL-10. In contrast, acute alcohol …

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 …

Induction And Regulation Of Monocyte Procoagulant Activity, Gyongyi Szabo, Carol Miller-Graziano

Gyongyi Szabo

Monocyte (MO) procoagulant activity (PCA) is induced by various stimuli including allogeneic stimulation, immunocomplexes, and bacterial products. Antigen-antibody complex stimulation therefore represents a pathway for MO PCA induction. Activation of MO PCA has been demonstrated in immunocomplex disease and could represent a major pathology in transplanted immunocomplex disease patients. Stimulation of monocytes via their FcRI receptor has been demonstrated to induce TNF and PGE2. This report demonstrates that stimulation of the high-density FcRI receptor-bearing (FcRI+) MO by resetting with anti-Rh coated erythrocytes also induces significant PCA levels (P less than 0.001). Muramyl dipeptide (MDP), a Gram-positive bacterial cell wall analogue, …

The Opposite Effects Of Acute And Chronic Alcohol On Lipopolysaccharide-Induced Inflammation Are Linked To Irak-M In Human Monocytes, Pranoti Mandrekar, Shashi Bala, Donna Catalano, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

Impaired host defense after alcohol use is linked to altered cytokine production, however, acute and chronic alcohol differently modulate monocyte/macrophage activation. We hypothesized that in human monocytes, acute alcohol induces hyporesponsiveness to LPS, resulting in decreased TNF-alpha, whereas chronic alcohol increases TNF-alpha by sensitization to LPS. We found that acute alcohol increased IL-1R-associated kinase-monocyte (IRAK-M), a negative regulator of IRAK-1, in human monocytes. This was associated with decreased IkappaB alpha kinase activity, NFkappaB DNA binding, and NFkappaB-driven reporter activity after LPS stimulation. In contrast, chronic alcohol decreased IRAK-M expression but increased IRAK-1 and IKK kinase activities, NFkappaB DNA binding, and …

Innate Immune Response And Hepatic Inflammation, Gyongyi Szabo, Pranoti Mandrekar, Angela Dolganiuc

Gyongyi Szabo

Inflammation is a pathogenic component of various types of acute and chronic liver diseases, and it contributes to progressive liver damage and fibrosis. Cells of the innate immune system initiate and maintain hepatic inflammation though mediator production as a result of their activation by pathogen-derived products recognized by pattern recognition receptors. Innate immune cells, particularly dendritic cells, have a pivotal role in sensing pathogens and initiating adaptive immune responses by activation and regulation of T-lymphocyte responses. Although the liver provides a "tolerogenic" immune environment for antigen-specific T-cells, activation of Kupffer cells, recruited macrophages, and inflammatory cells results in production of …

Acute Ethanol Treatment Augments Interleukin-12 Production In Activated Human Monocytes, Gyongyi Szabo, Linda Girouard, Pranoti Mandrekar, Donna Catalano

Gyongyi Szabo

No abstract provided.

Myeloid Dendritic Cells Of Patients With Chronic Hcv Infection Induce Proliferation Of Regulatory T Lymphocytes, Angela Dolganiuc, Edward Paek, Karen Kodys, Joanne Thomas, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND and AIMS: Dendritic cells (DCs) initiate and sustain an efficient T-lymphocyte response. Chronic hepatitis C virus (HCV) infection is associated with inefficient T-cell functions that fail to eradicate the virus, so defects in DC function might be involved in HCV pathogenesis. This study analyzed the activities of myeloid DCs and distinct CD4(+) T-cell populations in samples collected from patients with HCV. METHODS: The abilities of primary BDCA1(+) or monocyte-derived DCs from HCV patients (HCV-DC) to stimulate CD4(+), CD4(+)CD25(-), or different ratios of CD4(+)CD25(+)/CD4(+)CD25(-) T cells were evaluated in mixed lymphocyte reactions. T-cell proliferation and phenotype were evaluated by flow …

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, Gyongyi Szabo, Serena Chang, Angela Dolganiuc

Gyongyi Szabo

No abstract provided.

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 …

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 …

Liver In Sepsis And Systemic Inflammatory Response Syndrome, Gyongyi Szabo, Laszlo Romics, Gyorgy Frendl

Gyongyi Szabo

In patients with sepsis and SIRS, the liver has two opposing roles: a source of inflammatory mediators and a target organ for the effects of the inflammatory mediators. The liver is pivotal in modulating the systemic response to severe infection, because it contains the largest mass of macrophages (Kupffer cells) in the body; these macrophages can clear the endotoxin and bacteria that initiate the systemic inflammatory response. This article summarizes the functional changes that take place in the liver during sepsis and systemic inflammatory response syndrome and discusses the cellular and molecular mechanisms that underlie clinical outcomes.

Elevated Tumor Necrosis Factor Alpha Production Concomitant To Elevated Prostaglandin E2 Production By Trauma Patients' Monocytes, Thomas Takayama, Carol Miller-Graziano, Gyongyi Szabo

Gyongyi Szabo

The level of tumor necrosis factor alpha (TNF alpha), a monokine implicated in mediating septic shock, is elevated in the blood of some patients with sepsis. Monocytes from 11 trauma patients and 11 burn patients were suboptimally stimulated with interferon gamma and muramyl dipeptide, an analogue of bacterial wall products. The patients with sepsis showed significantly greater total TNF alpha levels (secreted in combination with cell-associated) 3 days before septic episodes, as compared with normal controls (32.38 to 2231.76 ng/10(6) monocytes per milliliter, median = 121.03 ng/10(6) monocytes per milliliter; normal control: 0.00 to 18.20 ng/10(6) monocytes per milliliter, median …

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 …

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 …

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, 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, 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.