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MTG16 contributes to colonic epithelial integrity in experimental colitis
  1. Christopher S Williams1,2,3,4,
  2. Amber M Bradley1,
  3. Rupesh Chaturvedi1,4,
  4. Kshipra Singh1,4,
  5. Maria B Piazuelo1,
  6. Xi Chen5,
  7. Elizabeth M McDonough6,
  8. David A Schwartz1,
  9. Caroline T Brown1,
  10. Margaret M Allaman1,
  11. Lori A Coburn1,4,
  12. Sara N Horst1,4,
  13. Dawn B Beaulieu1,
  14. Yash A Choksi1,
  15. Mary Kay Washington7,
  16. Amanda D Williams1,
  17. Melissa A Fisher8,
  18. Sandra S Zinkel2,3,
  19. Richard M Peek Jr1,3,4,
  20. Keith T Wilson1,2,3,4,
  21. Scott W Hiebert3,8
  1. 1Department of Medicine, Division of Gastroenterology, Vanderbilt University, Nashville, Tennessee, USA
  2. 2Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA
  3. 3Vanderbilt Ingram Cancer Center, Nashville, Tennessee, USA
  4. 4Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
  5. 5Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA
  6. 6Department of Pediatrics, Division of Pediatric Gastroenterology, Vanderbilt University, Nashville, Tennessee, USA
  7. 7Department of Pathology, Vanderbilt University, Nashville, Tennessee, USA
  8. 8Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, USA
  1. Correspondence to Dr Christopher S Williams, Assistant Professor of Medicine/Gastroenterology, Assistant Professor of Cancer Biology, Vanderbilt University School of Medicine, B2215 Garland Ave. 1065D MRB-IV, Nashville, TN 37232-0252, USA; christopher.williams{at}vanderbilt.edu

Abstract

Objective The myeloid translocation genes (MTGs) are transcriptional corepressors with both Mtg8−/− and Mtgr1−/− mice showing developmental and/or differentiation defects in the intestine. We sought to determine the role of MTG16 in intestinal integrity.

Methods Baseline and stress induced colonic phenotypes were examined in Mtg16−/− mice. To unmask phenotypes, we treated Mtg16−/− mice with dextran sodium sulphate (DSS) or infected them with Citrobacter rodentium and the colons were examined for ulceration and for changes in proliferation, apoptosis and inflammation.

Results Mtg16−/− mice have altered immune subsets, suggesting priming towards Th1 responses. Mtg16−/− mice developed increased weight loss, diarrhoea, mortality and histological colitis and there were increased innate (Gr1+, F4/80+, CD11c+ and MHCII+; CD11c+) and Th1 adaptive (CD4) immune cells in Mtg16−/− colons after DSS treatment. Additionally, there was increased apoptosis and a compensatory increased proliferation in Mtg16−/− colons. Compared with wild-type mice, Mtg16−/− mice exhibited increased colonic CD4;IFN-γ cells in vehicle-treated and DSS-treated mice. Adoptive transfer of wild-type marrow into Mtg16−/− recipients did not rescue the Mtg16−/− injury phenotype. Isolated colonic epithelial cells from DSS-treated Mtg16−/− mice exhibited increased KC (Cxcl1) mRNA expression when compared with wild-type mice. Mtg16−/− mice infected with C rodentium had more severe colitis and greater bacterial colonisation. Last, MTG16 mRNA levels were reduced in human ulcerative colitis versus normal colon tissues.

Conclusions These observations indicate that MTG16 is critical for colonocyte survival and regeneration in response to intestinal injury and provide evidence that this transcriptional corepressor regulates inflammatory recruitment in response to injury.

  • Colitis
  • ulcerative
  • dextran sulphate sodium
  • wound-healing
  • Mtg16
  • immunity
  • cancer
  • inflammatory bowel disease
  • experimental colitis
  • IBD
  • IBD—genetics
  • IBD basic research
  • intestinal T cells
  • gene expression
  • colorectal diseases
  • colon carcinogenesis
  • cytokines
  • Helicobacter pylori
  • inflammatory mechanisms
  • gastrointestinal pathology
  • angiogenesis
  • carcinogenesis
  • colorectal cancer
  • Crohn's colitis
  • Helicobacter pylori infection
  • matrix metalloproteinase
  • Helicobacter pylori—pathogenesis
  • bacterial pathogenesis

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Footnotes

  • Funding Supported by the National Institutes of Health grants DK080221 (CSW), CA64140 (SWH), HL088494 (SWH), P50CA095103 (MKW), AT004821 (KTW), AT004821-S1 (KTW), DK053620 (KTW), a Merit Review Grant from the Office of Medical Research, Department of Veterans Affairs (KTW and CSW) and ACS-RSG 116552 (CSW). Core Services performed through Vanderbilt University Medical Center's Digestive Disease Research Center supported by NIH grant P30DK058404 (RMP) and the Vanderbilt Ingram Cancer Center shared resources P30CA068485 as well as the National Center for Research Resources, Grant UL1 RR024975-01, and is now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06.

  • Disclosure DAS: Abbott: grant support, consultant; UCB: grant support, consultant; BrainTree Labs: consultant.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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