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

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State: Public
Version: author
Serval ID
serval:BIB_CF53C5F6A99C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy.
Journal
Inflammatory Bowel Diseases
Author(s)
Scharl Michael, Mwinyi Jessica, Fischbeck Anne, Leucht Katharina, Eloranta Jyrki J., Arikkat Joba, Pesch Theresa, Kellermeier Silvia, Mair Alma, Kullak-Ublick Gerd A., Truninger Kaspar, Noreen Faiza, Regula Jaroslaw, Gaj Pawel, Pittet Valerie, Mueller Christoph, Hofmann Claudia, Fried Michael, McCole Declan F., Rogler Gerhard
ISSN
1536-4844 (Electronic)
ISSN-L
1078-0998
Publication state
Published
Issued date
2012
Peer-reviewed
Oui
Volume
18
Number
5
Pages
900-912
Language
english
Notes
Publication types: Comparative Study ; Journal Article
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 T(84) 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, T(84) 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.
Keywords
Acetylmuramyl-Alanyl-Isoglutamine/pharmacology, Adjuvants, Immunologic/pharmacology, Adult, Autophagy, Blotting, Western, Case-Control Studies, Cells, Cultured, Cohort Studies, Colon/cytology, Colon/drug effects, Crohn Disease/genetics, Crohn Disease/immunology, Cytokines/secretion, DNA/blood, DNA/genetics, Female, Fluorescent Antibody Technique, Genotype, Haplotypes/genetics, Humans, Immunoenzyme Techniques, Immunoprecipitation, Interferon-gamma/secretion, Male, Mitogen-Activated Protein Kinases/genetics, Mitogen-Activated Protein Kinases/metabolism, Monocytes/cytology, Monocytes/drug effects, Nod2 Signaling Adaptor Protein/genetics, Nod2 Signaling Adaptor Protein/metabolism, Phosphorylation/drug effects, Polymorphism, Single Nucleotide/genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 2/antagonists & inhibitors, Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics, RNA, Messenger/genetics, RNA, Small Interfering/genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, T-Box Domain Proteins/genetics, T-Box Domain Proteins/metabolism, Tumor Markers, Biological/genetics
Pubmed
Web of science
Create date
27/10/2011 14:16
Last modification date
20/08/2019 16:49
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