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Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy

Authors

  • Michael Scharl MD,

    Corresponding author
    1. Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
    2. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
    • Division of Gastroenterology and Hepatology, University Hospital Zürich, 8091 Zürich, Switzerland
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  • Jessica Mwinyi MD, PhD,

    1. Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
    2. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
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  • Anne Fischbeck PhD,

    1. Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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  • Katharina Leucht,

    1. Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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  • Jyrki J. Eloranta PhD,

    1. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
    2. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
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  • Joba Arikkat,

    1. Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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  • Theresa Pesch,

    1. Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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  • Silvia Kellermeier,

    1. Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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  • Alma Mair,

    1. Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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  • Gerd A. Kullak-Ublick MD,

    1. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
    2. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
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  • Kaspar Truninger MD,

    1. Medical Clinic, SRO Hospital Langenthal, Langenthal, Switzerland
    2. Department of Biomedicine, Institute of Biochemistry and Genetics, University of Basel, Switzerland
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  • Faiza Noreen PhD,

    1. Department of Biomedicine, Institute of Biochemistry and Genetics, University of Basel, Switzerland
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  • Jaroslaw Regula MD,

    1. Department of Gastroenterology, Medical Centre for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw, Poland
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  • Pawel Gaj PhD,

    1. Department of Gastroenterology, Medical Centre for Postgraduate Education, Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw, Poland
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  • Valerie Pittet PhD,

    1. Health Care Evaluation Unit, Institute of Social and Preventive Medicine (IUMSP), CHUV, Lausanne, Switzerland
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  • Christoph Mueller MD,

    1. Institute of Pathology, Division of Immunopathology, University of Berne, Berne, Switzerland
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  • Claudia Hofmann PhD,

    1. Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
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  • Michael Fried MD,

    1. Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
    2. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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  • Declan F. McCole PhD,

    1. Division of Gastroenterology, University of California, San Diego, School of Medicine, La Jolla, California, USA
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  • Gerhard Rogler MD, PhD

    1. Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
    2. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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  • Supported by an educational grant from Essex Chemie, Switzerland (to M.S.), a research grant from the European Crohn's and Colitis Organisation (ECCO) (to M.S.), a research credit from the University of Zurich (to M.S.), a grant from the Swiss Philanthropy Foundation (to M.S. and G.R.), a grant from the Baumgarten Foundation (to G.R.), research grants from the Swiss National Science Foundation (SNF) Grant No. 310030-120312 (to G.R.), and the Swiss IBD Cohort (Grant No. 3347CO-108792), by the Zurich Center for Integrative Human Physiology (ZIHP) of the University of Zurich and by a Senior Research Award from the Crohn's and Colitis Foundation of America (CCFA) (to D.F.M.).

Abstract

Background:

The single nucleotide polymorphism (SNP) rs2542151 within the gene locus region encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) has been associated with Crohn's disease (CD), ulcerative colitis (UC), type-I diabetes, and rheumatoid arthritis. We have previously shown that PTPN2 regulates mitogen-activated protein kinase (MAPK) signaling and cytokine secretion in human THP-1 monocytes and intestinal epithelial cells (IEC). Here, we studied whether intronic PTPN2 SNP rs1893217 regulates immune responses to the nucleotide-oligomerization domain 2 (NOD2) ligand, muramyl-dipeptide (MDP).

Materials and Methods:

Genomic DNA samples from 343 CD and 663 non-IBD control patients (male and female) from a combined German, Swiss, and Polish cohort were genotyped for the presence of the PTPN2 SNPs, rs2542151, and rs1893217. PTPN2-variant rs1893217 was introduced into T84 IEC or THP-1 cells using a lentiviral vector.

Results:

We identified a novel association between the genetic variant, rs1893217, located in intron 7 of the PTPN2 gene and CD. Human THP-1 monocytes carrying this variant revealed increased MAPK activation as well as elevated mRNA expression of T-bet transcription factor and secretion of interferon-γ in response to the bacterial wall component, MDP. In contrast, secretion of interleukin-8 and tumor necrosis factor were reduced. In both, T84 IEC and THP-1 monocytes, autophagosome formation was impaired.

Conclusions:

We identified a novel CD-associated PTPN2 variant that modulates innate immune responses to bacterial antigens. These findings not only provide key insights into the effects of a functional mutation on a clinically relevant gene, but also reveal how such a mutation could contribute to the onset of disease. (Inflamm Bowel Dis 2011;)

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