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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.

SUBMITTER: Takyar S

PROVIDER: S-EPMC3782056 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis.

Takyar Seyedtaghi S Vasavada Hema H Zhang Jian-ge JG Ahangari Farida F Niu Naiqian N Liu Qing Q Lee Chun Geun CG Cohn Lauren L Elias Jack A JA

The Journal of experimental medicine 20130916 10

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 Th ...[more]

PMID: 24043765

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Project description:Long non‑coding RNA 00460 (LINC00460) has been reported to be involved in the tumorigenesis of various cancer types. However, the function of LINC00460 in acute myeloid leukemia (AML) remains elusive. Therefore, the present study aimed to investigate the role of LINC00460 in AML. The expression of LINC00460 in the serum of 80 diagnosed patients with AML and 67 healthy controls was measured via reverse transcription‑quantitative polymerase chain reaction, and the results were compared with clinical features and patient outcomes. The expression of LINC00460 in 45 patients with cytogenetically normal‑AML (CN‑AML) was also assayed. Receiver operating characteristic (ROC) curves were generated to evaluate the sensitivity and specificity of serum LINC00460. In addition, the effects of LINC00460 on the viability, cell cycle distribution and apoptosis of AML cells were investigated. Bioinformatics tools were used to identify the possible mechanisms of how LINC00460 affects AML cells. It was found that the expression of LINC00460 was significantly upregulated in the serum of patients with AML and those with CN‑AML. Higher expression of serum LINC00460 was positively associated with French‑American‑British classification and cytogenetics. Furthermore, ROC curve analyses demonstrated that serum LINC00460 could differentiate patients with AML from healthy individuals with an area under the curve of 0.8488 (95% CI, 0.7697‑0.9279). The serum LINC00460 expression was also significantly decreased when the patients achieved complete remission. Kaplan‑Meier analysis indicated that patients with high serum LINC00460 expression had a shorter overall survival time compared with the low serum LINC00460 expression group. Knockdown of LINC00460 inhibited viability, while inducing cell cycle arrest and apoptosis in AML cells. LINC00460 was also a decoy of microRNA (miR)‑320b, which can further inhibit the expression of PBX homeobox 3 (PBX3). Collectively, the results suggested that LINC00460 may be applied as a potential diagnostic and prognostic biomarker for patients with AML. It was identified that LINC00460 may exert its effects, at least partly, via the miR‑320b/PBX3 axis in AML.

Dataset Information

VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis.

Publications

VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis.

Similar Datasets

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