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Chronic Ethanol Consumption Modulates Growth Factor Release, Mucosal Cytokine Production, and Micro RNA Expression in Nonhuman Primates
Author(s) -
Asquith Mark,
Pasala Sumana,
Engelmann Flora,
Haberthur Kristen,
Meyer Christine,
Park Byung,
Grant Kathleen A.,
Messaoudi Ilhem
Publication year - 2014
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12325
Subject(s) - cytokine , hepatocyte growth factor , vascular endothelial growth factor , biology , peripheral blood mononuclear cell , growth factor , stat3 , microrna , transcription factor , immunology , immune system , endocrinology , cancer research , medicine , microbiology and biotechnology , signal transduction , in vitro , receptor , biochemistry , vegf receptors , gene
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 T h1 and T h17 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 T h1/ T h17 cytokine production, we compared expression levels of micro RNA s in PBMC and intestinal mucosa. Our analysis revealed EtOH‐dependent up‐regulation of distinct micro RNA s in affected tissues (mi R ‐181a and mi R ‐221 in PBMC ; mi R ‐155 in colon). Moreover, we were able to detect reduced expression of the transcription factors STAT 3 and ARNT , which regulate expression of VEGF , G ‐ CSF , and HGF and contain targets for these micro RNA s. To confirm and extend these observations, PBMC were transfected with either mimics or antagomirs of mi R ‐181 and mi R ‐221, and protein levels of the transcription factors and growth factors were determined. Transfection of micro RNA mimics led to a reduction in both STAT 3/ ARNT as well as VEGF / HGF / G ‐ CSF levels. The opposite outcome was observed when micro RNA antagomirs were transfected. Conclusions Chronic EtOH consumption significantly disrupts both peripheral and mucosal immune homeostasis, and this dysregulation may be mediated by changes in micro RNA expression.