Medicine and Health Sciences Commons^™

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 …

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 …

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 …

Nf-Kb, A Prototypical Cytokine-Regulated Transcription Factor: Implications For Alcohol-Mediated Responses, Samir Zakhari, Gyongyi Szabo

Gyongyi Szabo

Summary of the presentations and discussions held at the symposium NF-KB, a Prototypical Cytokine-Regulated Transcription Factor: Implications for Alcohol-Mediated Responses, held during the Joint RSMSBRA meeting in Washington, D.C. in June 1996.

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.

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, …

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, 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 …

Viral And Host Factors Induce Macrophage Activation And Loss Of Toll-Like Receptor Tolerance In Chronic Hcv Infection, Angela Dolganiuc, Oxana Norkina, Karen Kodys, Donna Catalano, Gennadiy Bakis, Christopher Marshall, Pranoti Mandrekar, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND and AIMS: Persistent inflammation contributes to progression of liver damage in chronic HCV (cHCV) infection. Repeated exposure to toll-like receptor (TLR) ligands results in tolerance, a protective mechanism aimed at limiting inflammation.

METHODS: Monocytes/macrophages were repeatedly stimulated via proinflammatory cytokine-inducing TLRs and evaluated for activation markers.

RESULTS: Unlike monocytes of controls or patients with nonalcoholic steatohepatitis, the monocytes of cHCV patients were hyperresponsive and failed to show homo- or heterotolerance to TLR ligands, manifested by elevated tumor necrosis factor (TNF)-alpha production. Serum levels of interferon (IFN)-gamma, endotoxin (TLR4 ligand), and HCV core protein (TLR2 ligand) were elevated in cHCV …

Ethanol-Mediated Regulation Of Transcription Factors In Immunocompetent Cells, Gyongyi Szabo, Pranoti Mandrekar

Gyongyi Szabo

The immunomodulatory effects of acute and chronic alcohol use are characterized by impaired antigen-specific immune activation and by increased susceptibility to infections due to alterations in innate immune responses and inflammatory mediator production. The central feature of cellular responses to inflammatory and stress signals is the activation of the nuclear regulatory kappa B/Rel family of transcriptional factors via various surface receptor systems in immunocompetent cells. Activation of NF-kappa B, however, is regulated at multiple levels including I-kappa B degradation, nuclear translocation, and by interaction of NF-kappa B/Rel with other transcription factors. Data from our and other laboratories demonstrate that acute …

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 …

Inhibition Of Lipopolysaccharide-Mediated Nfkappab Activation By Ethanol In Human Monocytes, Pranoti Mandrekar, Donna Catalano, Gyongyi Szabo

Gyongyi Szabo

Alcohol use is typically associated with impaired immunity and increased host susceptibility to infection, partially due to decreased inflammatory response. Acute ethanol exposure has been shown to down-regulate monocyte production of inflammatory cytokines. Activation of the pluripotent transcription factor NFkappaB is a pivotal step in the induction of inflammatory cytokines, chemokines and growth factors. Therefore, we hypothesized that alcohol may alter NFkappaB activation, thus providing a mechanism for the decreased inflammatory cytokine production by monocytes after acute alcohol treatment. We show here for the first time that alcohol inhibits lipopolysaccharide (LPS)-induced NFkappaB activation in human monocytes by decreasing DNA binding …