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Chronic Ethanol Consumption Modulates Growth Factor Release, Mucosal Cytokine Production, and MicroRNA Expression in Nonhuman Primates

Authors

  • Mark Asquith,

    1. Division of Pathobiology and Immunology , Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon
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    • These authors contributed equally to this study.

  • Sumana Pasala,

    1. Division of Biomedical Sciences , School of Medicine, University of California-Riverside, Riverside, California
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    • These authors contributed equally to this study.

  • Flora Engelmann,

    1. Division of Pathobiology and Immunology , Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon
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  • Kristen Haberthur,

    1. Department of Molecular Microbiology and Immunology , Oregon Health and Science University, Portland, Oregon
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  • Christine Meyer,

    1. Division of Pathobiology and Immunology , Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon
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  • Byung Park,

    1. Division of Biostatistics , Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, Oregon
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  • Kathleen A. Grant,

    1. Department of Behavioral Neuroscience , Oregon Health and Science University, Portland, Oregon
    2. Division of Neuroscience , Oregon National Primate Research Center, Beaverton, Oregon
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  • Ilhem Messaoudi

    Corresponding author
    1. Division of Pathobiology and Immunology , Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon
    2. Division of Biomedical Sciences , School of Medicine, University of California-Riverside, Riverside, California
    3. Department of Molecular Microbiology and Immunology , Oregon Health and Science University, Portland, Oregon
    4. Division of Neuroscience , Oregon National Primate Research Center, Beaverton, Oregon
    • Reprint requests: Ilhem Messaoudi, PhD, University of California-Riverside, 900 University Avenue, Riverside, CA 92521; Tel.: 951-827-7774; Fax: 951-827-0774; E-mail: messaoud@ucr.edu

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Abstract

Background

Chronic alcohol consumption has been associated with enhanced susceptibility to both systemic and mucosal infections. However, the exact mechanisms underlying this enhanced susceptibility remain incompletely understood.

Methods

Using a nonhuman primate model of ethanol (EtOH) self-administration, we examined the impact of chronic alcohol exposure on immune homeostasis, cytokine, and growth factor production in peripheral blood, lung, and intestinal mucosa following 12 months of chronic EtOH exposure.

Results

EtOH exposure inhibited activation-induced production of growth factors hepatocyte growth factor (HGF), granulocyte colony-stimulating factor (G-CSF), and vascular-endothelial growth factor (VEGF) by peripheral blood mononuclear cells (PBMC). Moreover, EtOH significantly reduced the frequency of colonic Th1 and Th17 cells in a dose-dependent manner. In contrast, we did not observe differences in lymphocyte frequency or soluble factor production in the lung of EtOH-consuming animals. To uncover mechanisms underlying reduced growth factor and Th1/Th17 cytokine production, we compared expression levels of microRNAs in PBMC and intestinal mucosa. Our analysis revealed EtOH-dependent up-regulation of distinct microRNAs in affected tissues (miR-181a and miR-221 in PBMC; miR-155 in colon). Moreover, we were able to detect reduced expression of the transcription factors STAT3 and ARNT, which regulate expression of VEGF, G-CSF, and HGF and contain targets for these microRNAs. To confirm and extend these observations, PBMC were transfected with either mimics or antagomirs of miR-181 and miR-221, and protein levels of the transcription factors and growth factors were determined. Transfection of microRNA mimics led to a reduction in both STAT3/ARNT as well as VEGF/HGF/G-CSF levels. The opposite outcome was observed when microRNA antagomirs were transfected.

Conclusions

Chronic EtOH consumption significantly disrupts both peripheral and mucosal immune homeostasis, and this dysregulation may be mediated by changes in microRNA expression.

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