Format

Send to:

Choose Destination
See comment in PubMed Commons below
Gastroenterology. 2014 Jul;147(1):184-195.e3. doi: 10.1053/j.gastro.2014.04.007. Epub 2014 Apr 13.

Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer.

Author information

  • 1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
  • 2Department of Pediatrics (Section of Molecular Genetics), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • 3Department of Pathology, Dallas VA Medical Center, Dallas, Texas.
  • 4Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany.
  • 5Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
  • 6Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas.
  • 7Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • 8Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany.
  • 9Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • 10Estonian Genome Center, University of Tartu, Tartu, Estonia.
  • 11Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
  • 12Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: ezra.burstein@utsouthwestern.edu.

Abstract

BACKGROUND & AIMS:

Activation of the transcription factor nuclear factor-κB (NF-κB) has been associated with the development of inflammatory bowel disease (IBD). Copper metabolism MURR1 domain containing 1 (COMMD1), a regulator of various transport pathways, has been shown to limit NF-κB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in human beings.

METHODS:

We created mice with a specific disruption of Commd1 in myeloid cells (Mye-knockout [K/O] mice); we analyzed immune cell populations and functions and expression of genes regulated by NF-κB. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate, and colitis-associated cancer was induced by administration of dextran sodium sulfate and azoxymethane. We measured levels of COMMD1 messenger RNA in colon biopsy specimens from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis.

RESULTS:

In comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed a reduced expression of COMMD1 in colon biopsy specimens and circulating leukocytes from patients with IBD. We associated single-nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis.

CONCLUSIONS:

Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.

Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

CD; Gene Regulation; Mouse Model; UC

PMID:
24727021
[PubMed - indexed for MEDLINE]
PMCID:
PMC4086320
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk