title: Chronic ethanol consumption modulates growth factor release, mucosal cytokine production, and microRNA expression in nonhuman primates.
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.
authors: Division of Pathobiology and Immunology , Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon.
authors: Mark
authors: M
authors: Asquith
authors: Sumana
authors: S
authors: Pasala
authors: Flora
authors: F
authors: Engelmann
authors: Kristen
authors: K
authors: Haberthur
authors: Christine
authors: C
authors: Meyer
authors: Byung
authors: B
authors: Park
authors: Kathleen A
authors: KA
authors: Grant
authors: Ilhem
authors: I
authors: Messaoudi
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D011323:Primates; D012646:Self Administration
chemical_list: D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D000431:Ethanol
keywords: Ethanol; Immunity; MicroRNA; Nonhuman Primate; Self-Administration