Asquith Mark, Pasala Sumana, Engelmann Flora, Haberthur Kristen, Meyer Christine, Park Byung, Grant Kathleen A, Messaoudi Ilhem
Division of Pathobiology and Immunology , Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon.
Alcohol Clin Exp Res. 2014 Apr;38(4):980-93. doi: 10.1111/acer.12325. Epub 2013 Dec 13.
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.
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.
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.
Chronic EtOH consumption significantly disrupts both peripheral and mucosal immune homeostasis, and this dysregulation may be mediated by changes in microRNA expression.
长期饮酒与全身感染和黏膜感染的易感性增加有关。然而，这种易感性增加背后的确切机制仍未完全明了。
使用乙醇（EtOH）自我给药的非人灵长类动物模型，我们研究了慢性酒精暴露12个月后，对免疫稳态、外周血、肺和肠黏膜中细胞因子及生长因子产生的影响。
EtOH暴露抑制外周血单个核细胞（PBMC）激活诱导的生长因子肝细胞生长因子（HGF）、粒细胞集落刺激因子（G-CSF）和血管内皮生长因子（VEGF）的产生。此外，EtOH以剂量依赖的方式显著降低结肠Th1和Th17细胞的频率。相比之下，我们未观察到饮酒动物肺中淋巴细胞频率或可溶性因子产生的差异。为揭示生长因子和Th1/Th17细胞因子产生减少的机制，我们比较了PBMC和肠黏膜中微小RNA的表达水平。我们的分析显示，受影响组织中不同微小RNA的EtOH依赖性上调（PBMC中的miR-181a和miR-221；结肠中的miR-155）。此外，我们能够检测到转录因子STAT3和ARNT的表达降低，它们调节VEGF、G-CSF和HGF的表达，并包含这些微小RNA的靶标。为证实并扩展这些观察结果，用miR-181和miR-221的模拟物或拮抗剂转染PBMC，并测定转录因子和生长因子的蛋白水平。转染微小RNA模拟物导致STAT3/ARNT以及VEGF/HGF/G-CSF水平降低。转染微小RNA拮抗剂时观察到相反的结果。
长期EtOH摄入显著破坏外周和黏膜免疫稳态，这种失调可能由微小RNA表达的变化介导。
