Hypoxia-Inducible Factor Augments Experimental Colitis Through an MIF–Dependent Inflammatory Signaling Cascade

Shah, Yatrik M.; Ito, Shinji; Morimura, Keiichirou; Chen, Chi; Yim, Sung Hye; Gonzalez, Frank J.

doi:10.1053/j.gastro.2008.03.009

Cited by 146 publications

(150 citation statements)

References 51 publications

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“…An increase in proinflammatory cytokines that contributes to the chronicity comes as a consequence of these ROS mediated mechanisms. Inflammation can induce a certain level of hypoxia which in turn can reinforce the inflammatory state essentially by the HIF-1 capacity of attracting macrophages that would increase the array of proinflammatory mediators (MIF, TNF, IL-6, IL-10) (Shah et al, 2008). HIF-1 can also affect histone code through HDAC2 inhibition (Charron et al, 2009) and the direct induction of H3K9 demethylases expression (Pollard et al, 2008).…”

Section: Inflammation Oxidative Stress and Hypoxiamentioning

confidence: 99%

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

Milagro

Mansego

Miguel

et al. 2013

Molecular Aspects of Medicine

247

161

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Nutritional factors play a life-long role in human health. Indeed, there is growing evidence that one of the mechanisms by which nutrients and bioactive compounds affect metabolic traits is epigenetics. Complex interactions among food components and histone modifications, DNA methylation, non-coding RNA expression and chromatin remodeling factors lead to a dynamic regulation of gene expression that controls the cellular phenotype. Although perinatal period is the time of highest phenotypic plasticity, contributing largely to developmental programming, also during adulthood there is evidence about a nutritional influence on epigenetic regulation. Similarly to type 2 diabetes, hypertension, atherosclerosis and other metabolic disorders, obesity predisposition and weight loss outcomes have been repeatedly associated to changes in epigenetic patterns. Different non-nutritional risk factors that usually accompany obesity seem also to be involved in these epigenetic modifications, especially hyperglycemia, inflammation, hypoxia and oxidative stress. There are currently three major objectives in epigenetic research in relation to obesity: to search for epigenetic biomarkers to predict future health problems or detect the individuals at most risk, to understand the obesity-related environmental factors that could modulate gene expression by affecting epigenetic mechanisms, and to study novel therapeutic strategies based on nutritional or pharmacological agents that can modify epigenetic marks. At this level, the major tasks are: development of robust epigenetic biomarkers of weight regulation, description of those epigenetic marks more susceptible to be modified by dietary exposures, identification of the active ingredients (and the doses) that alter the epigenome, assessment of the real importance of other obesity-related factors on epigenetic regulation, determination of the period of life in which best results are obtained, and understanding of the importance of the inheritance of these epigenetic marks.

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Section: Inflammation Oxidative Stress and Hypoxiamentioning

confidence: 99%

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

Milagro

Mansego

Miguel

et al. 2013

Molecular Aspects of Medicine

247

161

View full text Add to dashboard Cite

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“…31 Although most studies support a protective role for HIF activation in inflammatory conditions of the gut, 27,44,45 its activation has also been proposed to be detrimental. 46 The cellular transcriptional response to hypoxia is not restricted to regulation by HIF and multiple other transcriptional pathways demonstrate hypoxic sensitivity. 47 Principal among the HIF-independent transcription factors, which display hypoxic sensitivity is NF-kB, a master regulator of innate immune and inflammatory gene expression.…”

Section: Inflammatory Bowel Disease (Ibd)mentioning

confidence: 99%

Hydroxylases as therapeutic targets in inflammatory bowel disease

Cummins

Doherty

Taylor

2013

Laboratory Investigation

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Inflammatory bowel disease (IBD) is a common and debilitating clinical disorder comprising ulcerative colitis and Crohn's disease. IBD occurs when inappropriate immunological activity in the intestinal mucosa results in epithelial barrier dysfunction leading to exposure of the mucosal immune system to luminal antigenic material. This in turn results in the cycles of inflammation and further barrier dysfunction which underlie disease progression. Although significant therapeutic advances have been made over the last decade, current immunosuppressive and anti-inflammatory treatments for IBD have significant limitations due to lack of treatment response in some patients and adverse effects, including increased risk of infection and malignancy. Recent studies using experimental models of IBD have identified that intracellular hydroxylases, a group of enzymes responsible for oxygen sensing and activation of adaptive transcriptional responses to hypoxia may represent a new class of therapeutic targets in IBD. Hydroxylase inhibitors are effective in ameliorating symptoms of colitis at least in part through the promotion of intestinal epithelial barrier function. The mechanism of this protection is due to activation of hypoxia-sensitive transcription factors, including the hypoxiainducible factor (HIF) and nuclear factor kappa-B (NF-kB), which activate specific epithelial barrier-protective transcriptional programs. In this review, the mechanism(s) of action and the therapeutic potential of small molecule hydroxylase inhibitors for the treatment of IBD will be discussed.

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“…Restoration of intestinal homeostasis requires several factors, including epithelial cell proliferation and differentiation, vesicle trafficking, protein secretion, integrity of the unfolded protein response pathways, and immune signaling (4)(5)(6)(7)(8). The essential molecular components required for a physiological response to the damage caused by DSS can be revealed by random germline mutagenesis (4).…”

mentioning

confidence: 99%

Creatine maintains intestinal homeostasis and protects against colitis

Turer

McAlpine

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Creatine, a nitrogenous organic acid, replenishes cytoplasmic ATP at the expense of mitochondrial ATP via the phosphocreatine shuttle. Creatine levels are maintained by diet and endogenous synthesis from arginine and glycine. Glycine amidinotransferase (GATM) catalyzes the rate-limiting step of creatine biosynthesis: the transfer of an amidino group from arginine to glycine to form ornithine and guanidinoacetate. We screened 36,530 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea–mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). Among 27 colitis susceptibility phenotypes identified and mapped, one was strongly correlated with a missense mutation in Gatm in a recessive model of inheritance, and causation was confirmed by CRISPR/Cas9 gene targeting. Supplementation of homozygous Gatm mutants with exogenous creatine ameliorated the colitis phenotype. CRISPR/Cas9-targeted (Gatmc/c) mice displayed a normal peripheral immune response and immune cell homeostasis. However, the intestinal epithelium of the Gatmc/c mice displayed increased cell death and decreased proliferation during DSS treatment. In addition, Gatmc/c colonocytes showed increased metabolic stress in response to DSS with higher levels of phospho-AMPK and lower levels of phosphorylation of mammalian target of rapamycin (phospho-mTOR). These findings establish an in vivo requirement for rapid replenishment of cytoplasmic ATP within colonic epithelial cells in the maintenance of the mucosal barrier after injury.

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Hypoxia-Inducible Factor Augments Experimental Colitis Through an MIF–Dependent Inflammatory Signaling Cascade

Abstract: The present study shows that a chronic increase in HIF signaling in the colon epithelial cells initiates a hyperinflammatory reaction that may have important implications in developing therapeutic strategies for inflammatory bowel disease.

Cited by 146 publications

References 51 publications

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

Hydroxylases as therapeutic targets in inflammatory bowel disease

Creatine maintains intestinal homeostasis and protects against colitis

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