title: Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Lillienne
authors.initials: L
authors.lastname: Chan
authors.affiliation: Department of Pediatrics (Section of Molecular Genetics), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Paulina
authors.initials: P
authors.lastname: Bartuzi
authors.affiliation: Department of Pathology, Dallas VA Medical Center, Dallas, Texas.
authors.forename: Shelby D
authors.initials: SD
authors.lastname: Melton
authors.affiliation: Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Weber
authors.affiliation: Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Ben-Shlomo
authors.affiliation: Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Varol
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Megan
authors.initials: M
authors.lastname: Raetz
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Xicheng
authors.initials: X
authors.lastname: Mao
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Petro
authors.initials: P
authors.lastname: Starokadomskyy
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: van Sommeren
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Mokadem
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Schneider
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Reid
authors.initials: R
authors.lastname: Weisberg
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: William A
authors.initials: WA
authors.lastname: Faubion
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Felix
authors.initials: F
authors.lastname: Yarovinsky
authors.affiliation: Department of Pediatrics (Section of Molecular Genetics), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marten
authors.initials: M
authors.lastname: Hofker
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kracht
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Vincent
authors.initials: V
authors.lastname: Aguirre
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.affiliation: Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Nathan
authors.initials: N
authors.lastname: Gluck
authors.affiliation: Department of Pediatrics (Section of Molecular Genetics), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van de Sluis
authors.affiliation: Department 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.
authors.forename: Ezra
authors.initials: E
authors.lastname: Burstein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001397:Azoxymethane / Q000009:adverse effects; D001706:Biopsy; D016022:Case-Control Studies; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000503:physiopathology*; D015212:Inflammatory Bowel Diseases / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C480519:COMMD1 protein, human; C103799:Commd1 protein, mouse; D016328:NF-kappa B; D012333:RNA, Messenger; D016264:Dextran Sulfate; D001397:Azoxymethane
keywords: CD; Gene Regulation; Mouse Model; UC
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