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Neurotensin Promotes the Development of Colitis and Intestinal Angiogenesis via Hif-1?-miR-210 Signaling.

ABSTRACT: Neurotensin (NT) via its receptor 1 (NTR1) modulates the development of colitis, decreases HIF-1?/PHD2 interaction, stabilizes and increases HIF-1? transcriptional activity, and promotes intestinal angiogenesis. HIF-1? induces miR-210 expression, whereas miR-210 is strongly upregulated in response to NT in NCM460 human colonic epithelial cells overexpressing NTR1 (NCM460-NTR1). In this study, we examined whether NT activates a NTR1-HIF-1?-miR-210 cascade using in vitro (NCM460-NTR1 cells) and in vivo (transgenic mice overexpressing [HIF-1?-OE] or lacking HIF-1? [HIF-1?-knockout (KO)] in intestinal epithelial cells and mice lacking NTR1 [NTR1-KO]) models. Pretreatment of NCM460-NTR1 cells with the HIF-1? inhibitor PX-478 or silencing of HIF-1? (small interfering HIF-1?) attenuated miR-210 expression in response to NT. Intracolonic 2,4,6-trinitrobenzenesulfonic acid (TNBS) administration (2-d model) increased colonic miR-210 expression that was significantly reduced in NTR1-KO, HIF-1?-KO mice, and wild-type mice pretreated intracolonically with locked nucleic acid anti-miR-210. In contrast, HIF-1?-OE mice showed increased miR-210 expression at baseline that was further increased following TNBS administration. HIF-1?-OE mice had also exacerbated TNBS-induced neovascularization compared with TNBS-exposed wild-type mice. TNBS-induced neovascularization was attenuated in HIF-1?-KO mice, or mice pretreated intracolonically with anti-miR-210. Intracolonic anti-miR-210 also reduced colitis in response to TNBS (2 d). Importantly, miR-210 expression was increased in tissue samples from ulcerative colitis patients. We conclude that NT exerts its proinflammatory and proangiogenic effects during acute colitis via a NTR1-prolyl hydroxylase 2/HIF-1?-miR-210 signaling pathway. Our results also demonstrate that miR-210 plays a proinflammatory role in the development of colitis.

SUBMITTER: Bakirtzi K

PROVIDER: S-EPMC4868643 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Neurotensin Promotes the Development of Colitis and Intestinal Angiogenesis via Hif-1α-miR-210 Signaling.

Bakirtzi Kyriaki K Law Ivy Ka Man IK Xue Xiang X Iliopoulos Dimitrios D Shah Yatrik M YM Pothoulakis Charalabos C

Journal of immunology (Baltimore, Md. : 1950) 20160413 10

Neurotensin (NT) via its receptor 1 (NTR1) modulates the development of colitis, decreases HIF-1α/PHD2 interaction, stabilizes and increases HIF-1α transcriptional activity, and promotes intestinal angiogenesis. HIF-1α induces miR-210 expression, whereas miR-210 is strongly upregulated in response to NT in NCM460 human colonic epithelial cells overexpressing NTR1 (NCM460-NTR1). In this study, we examined whether NT activates a NTR1-HIF-1α-miR-210 cascade using in vitro (NCM460-NTR1 cells) and in ...[more]

PMID: 27076683

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Neurotensin Promotes the Development of Colitis and Intestinal Angiogenesis via Hif-1?-miR-210 Signaling.

Publications

Neurotensin Promotes the Development of Colitis and Intestinal Angiogenesis via Hif-1α-miR-210 Signaling.

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