Life 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 …

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.

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 …

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 …

Fcgammar Cross-Linking Mediates Nf-Kappab Activation, Reduced Antigen Presentation Capacity, And Decreased Il-12 Production In Monocytes Without Modulation Of Myeloid Dendritic Cell Development, Yvonne Drechsler, Sangeeta Chavan, Donna Catalano, Pranoti Mandrekar, Gyongyi Szabo

Gyongyi Szabo

Stimulation of monocytes (MO) through receptors for the Fc region of immunoglobulin G (FcgammaR) activates a variety of responses, including phagocytosis, antibody (Ab)-dependent cellular cytotoxicity, and production of cytokines. We previously reported that the MO subpopulation that expresses FcgammaR in high density produces high levels of tumor necrosis factor alpha (TNF-alpha) compared with FcgammaR-negative MO. Here, we show that cross-linking MO via FcgammaRI or FcgammaRII but not via FcgammaRIII activates nuclear regulatory factor-kappaB (NF-kappaB), a transcription factor involved in regulation of TNF-alpha. NF-kappaB activation peaked at 2.75 h after FcgammaRI cross-linking, involved p65 and p50 (heterodimer) and not c-rel-containing NF-kappaB …

Acute Alcohol Exposure Exerts Anti-Inflammatory Effects By Inhibiting Ikappab Kinase Activity And P65 Phosphorylation In Human Monocytes, Pranoti Mandrekar, Valentina Jeliazkova, Donna Catalano, Gyongyi Szabo

Gyongyi Szabo

Acute alcohol use is associated with impaired immune responses and decreased proinflammatory cytokine production. Our earlier studies have shown that acute alcohol intake inhibits NF-kappaB DNA binding in an IkappaBalpha-independent manner. We report using human peripheral blood monocytes and Chinese hamster ovary cells transfected with CD14 cells that acute alcohol treatment in vitro exerts NF-kappaB inhibition by disrupting phosphorylation of p65. Immunoprecipitation of p65 and IkappaBalpha revealed that acute alcohol exposure for 1 h decreased NF-kappaB-IkappaBalpha complexes in the cytoplasm. Phosphorylation of p65 at Ser(536) is mediated by IkappaB kinase (IKK)beta and is required for NF-kappaB-dependent cellular responses. We show …