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

Haiying Li, Lillienne Chan, Paulina Bartuzi, Shelby D. Melton, Axel Weber, Shani Ben-Shlomo, Chen Varol, Megan Raetz, Xicheng Mao, Petro Starokadomskyy, Suzanne Van Sommeren, Mohamad Mokadem, Heike Schneider, Reid Weisberg, Harm Jan Westra, Tõnu Esko, Andres Metspalu, Vinod Kumar, William Alvis Faubion, Felix YarovinskyMarten Hofker, Cisca Wijmenga, Michael Kracht, Lude Franke, Vincent Aguirre, Rinse K. Weersma, Nathan Gluck, Bart Van De Sluis, Ezra Burstein

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalGastroenterology
Volume147
Issue number1
DOIs
StatePublished - 2014

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Colitis
Copper
Inflammation
Inflammatory Bowel Diseases
Knockout Mice
Genes
Neoplasms
Myeloid Cells
Lipopolysaccharides
Gene Expression
Dextran Sulfate
Colon
Sepsis
Azoxymethane
Biopsy
Quantitative Trait Loci
Intraperitoneal Injections
Ulcerative Colitis
Punctures
Ligation

Keywords

  • CD
  • Gene Regulation
  • Mouse Model
  • UC

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer. / Li, Haiying; Chan, Lillienne; Bartuzi, Paulina; Melton, Shelby D.; Weber, Axel; Ben-Shlomo, Shani; Varol, Chen; Raetz, Megan; Mao, Xicheng; Starokadomskyy, Petro; Van Sommeren, Suzanne; Mokadem, Mohamad; Schneider, Heike; Weisberg, Reid; Westra, Harm Jan; Esko, Tõnu; Metspalu, Andres; Kumar, Vinod; Faubion, William Alvis; Yarovinsky, Felix; Hofker, Marten; Wijmenga, Cisca; Kracht, Michael; Franke, Lude; Aguirre, Vincent; Weersma, Rinse K.; Gluck, Nathan; Van De Sluis, Bart; Burstein, Ezra.

In: Gastroenterology, Vol. 147, No. 1, 2014.

Research output: Contribution to journalArticle

Li, H, Chan, L, Bartuzi, P, Melton, SD, Weber, A, Ben-Shlomo, S, Varol, C, Raetz, M, Mao, X, Starokadomskyy, P, Van Sommeren, S, Mokadem, M, Schneider, H, Weisberg, R, Westra, HJ, Esko, T, Metspalu, A, Kumar, V, Faubion, WA, Yarovinsky, F, Hofker, M, Wijmenga, C, Kracht, M, Franke, L, Aguirre, V, Weersma, RK, Gluck, N, Van De Sluis, B & Burstein, E 2014, 'Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer', Gastroenterology, vol. 147, no. 1. https://doi.org/10.1053/j.gastro.2014.04.007
Li, Haiying ; Chan, Lillienne ; Bartuzi, Paulina ; Melton, Shelby D. ; Weber, Axel ; Ben-Shlomo, Shani ; Varol, Chen ; Raetz, Megan ; Mao, Xicheng ; Starokadomskyy, Petro ; Van Sommeren, Suzanne ; Mokadem, Mohamad ; Schneider, Heike ; Weisberg, Reid ; Westra, Harm Jan ; Esko, Tõnu ; Metspalu, Andres ; Kumar, Vinod ; Faubion, William Alvis ; Yarovinsky, Felix ; Hofker, Marten ; Wijmenga, Cisca ; Kracht, Michael ; Franke, Lude ; Aguirre, Vincent ; Weersma, Rinse K. ; Gluck, Nathan ; Van De Sluis, Bart ; Burstein, Ezra. / Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer. In: Gastroenterology. 2014 ; Vol. 147, No. 1.
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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.",
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T1 - Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer

AU - Li, Haiying

AU - Chan, Lillienne

AU - Bartuzi, Paulina

AU - Melton, Shelby D.

AU - Weber, Axel

AU - Ben-Shlomo, Shani

AU - Varol, Chen

AU - Raetz, Megan

AU - Mao, Xicheng

AU - Starokadomskyy, Petro

AU - Van Sommeren, Suzanne

AU - Mokadem, Mohamad

AU - Schneider, Heike

AU - Weisberg, Reid

AU - Westra, Harm Jan

AU - Esko, Tõnu

AU - Metspalu, Andres

AU - Kumar, Vinod

AU - Faubion, William Alvis

AU - Yarovinsky, Felix

AU - Hofker, Marten

AU - Wijmenga, Cisca

AU - Kracht, Michael

AU - Franke, Lude

AU - Aguirre, Vincent

AU - Weersma, Rinse K.

AU - Gluck, Nathan

AU - Van De Sluis, Bart

AU - Burstein, Ezra

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - CD

KW - Gene Regulation

KW - Mouse Model

KW - UC

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