Haiying Li1, Lillienne Chan1, Paulina Bartuzi2, Shelby D Melton3, Axel Weber4, Shani Ben-Shlomo5, Chen Varol5, Megan Raetz6, Xicheng Mao1, Petro Starokadomskyy1, Suzanne van Sommeren7, Mohamad Mokadem1, Heike Schneider8, Reid Weisberg1, Harm-Jan Westra9, Tõnu Esko10, Andres Metspalu10, Vinod Kumar9, William A Faubion11, Felix Yarovinsky6, Marten Hofker2, Cisca Wijmenga9, Michael Kracht4, Lude Franke9, Vincent Aguirre1, Rinse K Weersma7, Nathan Gluck5, Bart van de Sluis2, Ezra Burstein12. 1. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. 2. Department of Pediatrics (Section of Molecular Genetics), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 3. Department of Pathology, Dallas VA Medical Center, Dallas, Texas. 4. Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany. 5. Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 6. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas. 7. Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 8. Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany. 9. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 10. Estonian Genome Center, University of Tartu, Tartu, Estonia. 11. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. 12. 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.
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.
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.
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