Journal article
Copper Metabolism Domain-Containing 1 Represses Genes That Promote Inflammation and Protects Mice From Colitis and Colitis-Associated Cancer
Gastroenterology (New York, N.Y. 1943), Vol.147(1), pp.184-195.e3
07/2014
DOI: 10.1053/j.gastro.2014.04.007
PMCID: PMC4086320
PMID: 24727021
Abstract
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.
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.
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.
Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.
Details
- Title: Subtitle
- Copper Metabolism Domain-Containing 1 Represses Genes That Promote Inflammation and Protects Mice From Colitis and Colitis-Associated Cancer
- Creators
- Haiying Li - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TexasMohamad Mokadem - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TexasLillienne Chan - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TexasPaulina Bartuzi - Department of Pediatrics (Section of Molecular Genetics), University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsShelby D Melton - Department of Pathology, Dallas VA Medical Center, Dallas, TexasAxel Weber - Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, GermanyShani Ben–Shlomo - Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelChen Varol - Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelMegan Raetz - Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TexasXicheng Mao - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TexasPetro Starokadomskyy - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TexasSuzanne van Sommeren - Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsHeike Schneider - Institute of Physiological Chemistry, Hannover Medical School, Hannover, GermanyReid Weisberg - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TexasHarm-Jan Westra - Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsTõnu Esko - Estonian Genome Center, University of Tartu, Tartu, EstoniaAndres Metspalu - Estonian Genome Center, University of Tartu, Tartu, EstoniaVinod Kumar - Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsWilliam A Faubion - Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MinnesotaFelix Yarovinsky - Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TexasMarten Hofker - Department of Pediatrics (Section of Molecular Genetics), University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsCisca Wijmenga - Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsMichael Kracht - Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, GermanyLude Franke - Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsVincent Aguirre - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TexasRinse K Weersma - Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsNathan Gluck - Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelBart van de Sluis - Department of Pediatrics (Section of Molecular Genetics), University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsEzra Burstein - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Resource Type
- Journal article
- Publication Details
- Gastroenterology (New York, N.Y. 1943), Vol.147(1), pp.184-195.e3
- Publisher
- Elsevier Inc
- DOI
- 10.1053/j.gastro.2014.04.007
- PMID
- 24727021
- PMCID
- PMC4086320
- ISSN
- 0016-5085
- eISSN
- 1528-0012
- Language
- English
- Date published
- 07/2014
- Academic Unit
- Gastroenterology and Hepatology; Internal Medicine
- Record Identifier
- 9984094752902771
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