Chronic Ethanol Consumption Modulates Growth Factor Release, Mucosal Cytokine Production, and MicroRNA Expression in Nonhuman Primates. (13th December 2013)

• Record Type: Journal Article
• Authors: Asquith, Mark; Pasala, Sumana; Engelmann, Flora; Haberthur, Kristen; Meyer, Christine; Park, Byung; Grant, Kathleen A.; Messaoudi, Ilhem
• Is Part Of: Alcoholism. Volume 38:Number 4(2014:Apr.)
• Page Start: 980
• Page End: 993
• Publication Date: 2013-12-13
• Subjects: Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.12325
• Languages: English
• ISSNs: 0145-6008

Abstract

<abstract abstract-type="main" id="acer12325-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="acer12325-sec-0001" sec-type="section"> <title>Background</title> <p>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.</p> </sec> <sec id="acer12325-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="acer12325-sec-0003" sec-type="section"> <title>Results</title> <p>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.</p> </sec> <sec id="acer12325-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Chronic EtOH consumption significantly disrupts both peripheral and mucosal immune homeostasis, and this dysregulation may be mediated by changes in microRNA expression.</p> </sec> </abstract>