title: VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis.
abstract: Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF-miR-1-Mpl-P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.
authors.affiliation: Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Seyedtaghi
authors.initials: S
authors.lastname: Takyar
authors.forename: Hema
authors.initials: H
authors.lastname: Vasavada
authors.forename: Jian-ge
authors.initials: JG
authors.lastname: Zhang
authors.forename: Farida
authors.initials: F
authors.lastname: Ahangari
authors.forename: Naiqian
authors.initials: N
authors.lastname: Niu
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
authors.forename: Lauren
authors.initials: L
authors.lastname: Cohn
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D004727:Endothelium / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D019007:P-Selectin / Q000235:genetics* / Q000378:metabolism; D011014:Pneumonia / Q000235:genetics* / Q000276:immunology*; D034622:RNA Interference; D053628:Receptors, Thrombopoietin / Q000235:genetics* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; C481270:Mpl protein, mouse; D019007:P-Selectin; D053628:Receptors, Thrombopoietin; D042461:Vascular Endothelial Growth Factor A
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