Medical Specialties Commons^™

Acetate Causes Alcohol Hangover Headache In Rats., Christina R Maxwell, Rebecca Jay Spangenberg, Jan B Hoek, Stephen D Silberstein, Michael L Oshinsky

Department of Neurology Faculty Papers

BACKGROUND: The mechanism of veisalgia cephalgia or hangover headache is unknown. Despite a lack of mechanistic studies, there are a number of theories positing congeners, dehydration, or the ethanol metabolite acetaldehyde as causes of hangover headache.

METHODS: We used a chronic headache model to examine how pure ethanol produces increased sensitivity for nociceptive behaviors in normally hydrated rats.

RESULTS: Ethanol initially decreased sensitivity to mechanical stimuli on the face (analgesia), followed 4 to 6 hours later by inflammatory pain. Inhibiting alcohol dehydrogenase extended the analgesia whereas inhibiting aldehyde dehydrogenase decreased analgesia. Neither treatment had nociceptive effects. Direct administration of acetate …

Cyanidin-3-Glucoside Inhibits Ethanol-Induced Invasion Of Breast Cancer Cells Overexpressing Erbb2, Mei Xu, Kimberly A. Bower, Siying Wang, Jacqueline A. Frank, Gang Chen, Min Ding, Shiow Wang, Xianglin Shi, Zunji Ke, Jia Luo

Internal Medicine Faculty Publications

BACKGROUND: Ethanol is a tumor promoter. Both epidemiological and experimental studies suggest that ethanol may enhance the metastasis of breast cancer cells. We have previously demonstrated that ethanol increased the migration/invasion of breast cancer cells expressing high levels of ErbB2. Amplification of ErbB2 is found in 20-30% of breast cancer patients and is associated with poor prognosis. We sought to identify agents that can prevent or ameliorate ethanol-induced invasion of breast cancer cells. Cyanidin-3-glucoside (C3G), an anthocyanin present in many vegetables and fruits, is a potent natural antioxidant. Ethanol exposure causes the accumulation of intracellular reactive oxygen species (ROS). This …

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 …

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 …

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 …

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 …

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

Gyongyi Szabo

No abstract provided.

Alcohol-Induced Regulation Of Nuclear Regulatory Factor-Kβ In Human Monocytes, Pranoti Mandrekar, Donna Catalano, Gyongyi Szabo

Gyongyi Szabo

Acute ethanol exposure has the capacity to modulate immune functions, particularly, to down regulate monocyte production of inflammatory cytokines. However, the intracellular mechanisms for these effects of ethanol are yet to be understood. Considering that nuclear regulatory factor-kβ (NF-KB)/Rel is a common regulatory element of the promoter region of the inflammatory cytokine genes, herein, we tested the hypothesis that acute ethanol affects NF-kB activation in human monocytes. Adherence-isolated monocytes showed constitutive DNA binding activity of NF-kB. A clinically relevant dose (25 mM) of acute ethanol treatment in vitro increased NF-kB binding activity in monocytes with a preferential induction of the …

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 …

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 …

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.

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, 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, …

Diverse Regulation Of Nf-Kappab And Peroxisome Proliferator-Activated Receptors In Murine Nonalcoholic Fatty Liver, Laszlo Romics, Karen Kodys, Angela Dolganiuc, Lucia Graham, Arumugam Velayudham, Pranoti Mandrekar, Gyongyi Szabo

Gyongyi Szabo

Fatty liver is highly sensitive to inflammatory activation. Peroxisome proliferator-activated receptors (PPAR) have anti-inflammatory effects and regulate lipid metabolism in the fatty liver. We hypothesized that fatty liver leads to endotoxin sensitivity through an imbalance between pro- and anti-inflammatory signals. Leptin-deficient, ob/ob mice and their lean littermates were challenged with single or double insults and pro- and anti-inflammatory pathways were tested on cytokine production and activation of nuclear regulatory factors NF-kappaB and peroxisome proliferator receptor element (PPRE). Ob/ob mice produced significantly higher serum tumor necrosis factor alpha (TNF-alpha) and interleukin (IL) 6 and showed increased hepatic NF-kappaB activation compared to …

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, …

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 …

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, …

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 …

Inhibition Of Antigen-Presenting Cell Functions By Alcohol: Implications For Hepatitis C Virus Infection, Gyongyi Szabo, Angela Dolganiuc, Pranoti Mandrekar, Bernadette White

Gyongyi Szabo

The mechanisms of alcohol-induced immunosuppression include defects in innate and adaptive immune responses. Monocytes and dendritic cells (DCs) link innate and adaptive immune responses as they recognize viral antigens and induce antigen-specific T-cell activation. We investigated the effects of alcohol on antigen-presenting cell functions. Acute alcohol consumption by healthy volunteers (vodka, 2 ml/kg) resulted in significantly reduced antigen-presenting cell function of monocyte-derived DCs. Reduced allostimulatory capacity of DCs treated with alcohol in vitro correlated with decreased co-stimulatory molecule (B7.1 and B7.2) expression, as well as with reduced interleukin (IL)-12 and increased IL-10 concentrations, in mixed lymphocyte cultures. Dendritic cells recognize …

Hepatitis C Infection And Alcohol Use: A Dangerous Mix For The Liver And Antiviral Immunity, Gyongyi Szabo, Costica Aloman, Stephen Polyak, Steven Weinman, Jack Wands, Samir Zakhari

Gyongyi Szabo

This article presents the proceedings of a symposium presented at the meeting of the Research Society on Alcoholism, held in Santa Barbara, California, in June 2005. The organizers and chairs were Sam Zakhari and Gyongyi Szabo. The presentations included (1) Mitochondrial Abnormalities Induced by Hepatitis C -Alcohol Interaction by Steven Weinman; (2) Effects of Acute and Chronic Ethanol on Innate Antiviral Signaling Pathways, Hepatitis C Replication, and Human Liver Cell Transcription by Stephen Polyak; (3) Ethanol Alters Dendritic Cell Function In Vivo and Impairs the Subsequent Cellular Immune Responses to Hepatitis C Proteins by Costica Aloman; and (4) Pathogenic Interactions …

Regulation Of Monocyte Il-12 Production: Augmentation By Lymphocyte Contact And Acute Ethanol Treatment, Inhibition By Elevated Intracellular Camp, Gyongyi Szabo, Linda Girouard, Pranoti Mandrekar, Donna Catalano

Gyongyi Szabo

IL-12, a monocyte-derived cytokine, is pivotal in activation of cellular immune response and inflammation. Both inflammatory response and cellular immunity are impaired by acute ethanol consumption. Here, we found that in vitro acute ethanol treatment (25-100 mM) results in a dose-dependent and significant increase of IL-12 in IFN-gamma (100 U/ml) plus Staphylococcal enterotoxin B (SEB; 1 microg/ml) stimulated monocytes and mononuclear cells but not in unstimulated cells from non-alcoholic blood donors. There was significantly greater IL-12 production in the MNC population compared to isolated Mphi (P < 0.001). Prevention of monocyte surface contact with either purified T lymphocytes or monocyte-depleted MNC resulted in a significant, 65+/-20%, decrease in IL-12 production regardless of IFN-gamma, SEB or ethanol stimulation suggesting that Mphi T-cell surface contact provides an additional signal for IL-12 production. In addition to cell surface contact, soluble mediators, particularly IL-10 and PGE2 may regulate IL-12 production. The cyclooxygenase inhibitor, Indomethacin (10(-6)M), augmented both IL-12 and IL-10 levels in isolated monocytes and mononuclear cells whether induced by medium, SEB or SEB plus 25 mM ethanol suggesting that regulation of IL-12 production via the cyclooxygenase pathway is independent of IL-10. Finally, elevation of intracellular cAMP levels by dbcAMP treatment consistently inhibited IL-12 as well as IL-10 production in monocytes induced by IFN-gamma or IFN-gamma plus 25 mM ethanol. These data suggest that augmentation of monocyte IL-12 by acute ethanol is not mediated via the cAMP pathway.

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)