HIF-1 in T cells ameliorated dextran sodium sulfate-induced murine colitis

Higashiyama, Masaaki; Hokari, Ryota; Hozumi, Hideaki; Kurihara, Chie; Ueda, Toshihide; Watanabe, Chikako; Tomita, Kengo; Nakamura, Mitsuyasu; Komoto, Shunsuke; Okada, Yoshikiyo; Kawaguchi, Atsushı; Nagao, Shigeaki; Suematsu, Makoto; Goda, Nobuhito; Miura, Soichiro

doi:10.1189/jlb.1011518

Cited by 57 publications

(71 citation statements)

References 37 publications

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“…Our observations are in agreement with previous reports showing decreased IFN-g secretion by TCR-triggered T cells in vitro in hypoxic conditions (1,15,16), as well as more severe colonic inflammation (16) and increased antibacterial effect in HIF-1a-deficient mice in a murine model of sepsis (1).…”

Section: Hif-1 Negatively Regulates Th1 Priming In Vivosupporting

confidence: 83%

Cutting Edge: Hypoxia-Inducible Factor 1 Negatively Regulates Th1 Function

Shehade

Acolty

Moser

et al. 2015

The Journal of Immunology

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Tissue hypoxia can occur in physiological and pathological conditions. When O2 availability decreases, the transcription factor hypoxia-inducible factor (HIF)-1α is stabilized and regulates cellular adaptation to hypoxia. The objective of this study was to test whether HIF-1α regulates T cell fate and to define the molecular mechanisms of this control. Our data demonstrate that Th1 cells lose their capacity to produce IFN-γ when cultured under hypoxia. HIF-1α−/− Th1 cells were insensitive to hypoxia, underlining a critical role for HIF-1α. Our results point to a role for IL-10, as suggested by the increased IL-10 expression at low O2 levels and the unchanged IFN-γ production by IL-10–deficient Th1 cells stimulated in hypoxic conditions. Accordingly, STAT3 phosphorylation is increased in Th1 cells under hypoxia, leading to enhanced HIF-1α transcription, which, in turn, may inhibit suppressor of cytokine signaling 3 transcription. This positive-feedback loop reinforces STAT3 activation and downregulates Th1 responses that may cause collateral damage to the host.

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Section: Hif-1 Negatively Regulates Th1 Priming In Vivosupporting

confidence: 83%

Cutting Edge: Hypoxia-Inducible Factor 1 Negatively Regulates Th1 Function

Shehade

Acolty

Moser

et al. 2015

The Journal of Immunology

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“…It has been reported that HIF-1 in T cells ameliorates DSSinduced colitis by controlling the balance of Tregs and T effector cells. 34 Treg-intrinsic HIF-1a is further required for an optimal Treg function to control colitis. 12 We now focused on the role of HIF-1a in DCs because they play a crucial role in regulating the immune response and are also involved in the pathogenesis of IBD.…”

Section: Hif Plays a Crucial Role In The Regulation Of Many Immune Cementioning

confidence: 99%

Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis

et al. 2016

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Dendritic cells (DCs) serve as a bridge between innate and adaptive immunity and help to maintain intestinal homeostasis. Inflammatory bowel disease (IBD) is associated with dysregulation of the mucosal immune response. The concomitant hypoxic inflammation in IBD will activate the transcription factor hypoxia-inducible factor-1 (HIF-1) to also drive gene expression in DCs. Recent studies have described a protective role for epithelial HIF-1 in mouse models of IBD. We investigated the role of HIF-1 in DC function in a dextran sodium sulfate (DSS)-induced model of murine colitis. Wild-type and dendritic cell-specific HIF-1α knockout mice were treated with 3% DSS for 7 days. Knockout of HIF-1α in DCs led to a significantly larger loss of body weight in mice with DSS-induced colitis than in control mice. Knockout mice exhibited more severe intestinal inflammation with increased levels of proinflammatory cytokines and enhanced production of mucin. Induction of regulatory T cells (Tregs) was impaired, and the number of forkhead box P3 (Foxp3) Tregs was diminished by dendritic HIF-1α knockout. Our findings demonstrate that in DCs HIF-1α is necessary for the induction of sufficient numbers of Tregs to control intestinal inflammation.

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“…However, the use of a PHD inhibitor (FG-4497), which stabilizes HIF-1a, had a beneficial influence on weight loss, histological modifications and TNF-a production in a murine model of TNBS-induced colitis (21) . T-cells that infiltrated the inflamed mucosa in IBD patients expressed more HIF-1a, and HIF-1a KO mice displayed more severe DSS-induced colonic inflammation (12) . Based on these positive reports, PHD inhibitors have been suggested for use as a potential therapeutic approach to treat IBD patients (7) .…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Interferes With Hypoxia Signaling During Colonic Inflammation

Caria

Moscato

Tomé

et al. 2014

Arq. Gastroenterol.

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-Context -Intestinal inflammation can induce a local reduction in oxygen levels that triggers an adaptive response centered on the expression of hypoxia-inducible factors (HIFs). Nitric oxide, a well-described inflammatory mediator, may interfere with hypoxia signaling. Objectives -We aimed to evaluate the role of nitric oxide in hypoxia signaling during colonic inflammation. Method -Colitis was induced by single (acute) or repeated (reactivated colitis) trinitrobenzenosulfonic acid administration in rats.In addition, one group of rats with reactivated colitis was also treated with Nw-Nitro-L-arginine methyl ester hydrochloride to block nitric oxide synthase. Colitis was assessed by macroscopic score and myeloperoxidase activity in the colon samples. Hypoxia was determined using the oxygen-dependent probe, pimonidazole. The expression of HIF-1a and HIF-induced factors (vascular endothelial growth factor -VEGF and apelin) was assessed using Western blotting. Results -The single or repeated administration of trinitrobenzenosulfonic acid to rats induced colitis which was characterized by a high macroscopic score and myeloperoxidase activity. Hypoxia was observed with both protocols. During acute colitis, HIF-1a expression was not increased, but VEGF and apelin were increased. HIF-1a expression was inhibited during reactivated colitis, and VEGF and apelin were not increased. Nw-Nitro-L-arginine methyl ester hydrochloride blockade during reactivated colitis restored HIF-1a, VEGF and apelin expression. Conclusions -Nitric oxide could interfere with hypoxia signaling during reactivated colitis inflammation modifying the expression of proteins regulated by HIF-1a. HEADINGS -Colitis. Hypoxia-inducible factor 1. Nitric oxide. NG-Nitroarginine methyl ester. Endothelial growth factors.

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HIF-1 in T cells ameliorated dextran sodium sulfate-induced murine colitis

Cited by 57 publications

References 37 publications

Cutting Edge: Hypoxia-Inducible Factor 1 Negatively Regulates Th1 Function

Cutting Edge: Hypoxia-Inducible Factor 1 Negatively Regulates Th1 Function

Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis

Nitric Oxide Interferes With Hypoxia Signaling During Colonic Inflammation

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