Journal Article

Crohn's Disease-associated Polymorphism Within the PTPN2 Gene Affects Muramyl-Dipeptide-induced Cytokine Secretion and Autophagy

Mwinyi, Jessica, Gaj, Pawel, Rogler, Gerhard, Truninger, Kaspar, Eloranta, Jyrki J., Fischbeck, Anne, Leucht, Katharina, Fried, Michael, Mair, Alma, Scharl, Michael, Hofmann, Claudia, Regula, Jaroslaw, Mueller, Christoph, McCole, Declan F., Arikkat, Joba, Kellermeier, Silvia, Pesch, Theresa, Noreen, Faiza, Pittet, Valerie, Kullak-Ublick, Gerd A.

2012

Overview

BackgroundThe 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.ResultsWe 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.ConclusionsWe 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.

• Publisher: Oxford University Press,Wiley Subscription Services, Inc., A Wiley Company
• Subject: Acetylmuramyl-Alanyl-Isoglutamine - pharmacology / Adjuvants, Immunologic - pharmacology / Adult / Autophagy / Biomarkers, Tumor - genetics / Blotting, Western / Case-Control Studies / Cells, Cultured / Cohort Studies / Colon - cytology / Colon - drug effects / Colon - metabolism / Crohn Disease - genetics / Crohn Disease - immunology / Crohn's disease / cytokine secretion / Cytokines / Cytokines - secretion / DNA - blood / DNA - genetics / Female / Fluorescent Antibody Technique / Genotype / Haplotypes - genetics / Humans / Immunoenzyme Techniques / Immunoprecipitation / Interferon-gamma - secretion / Kinases / Male / Mitogen-Activated Protein Kinases - genetics / Mitogen-Activated Protein Kinases - metabolism / Monocytes - cytology / Monocytes - drug effects / Monocytes - metabolism / Mutation / NOD2 / Nod2 Signaling Adaptor Protein - genetics / Nod2 Signaling Adaptor Protein - metabolism / Phosphorylation - drug effects / Polymorphism / Polymorphism, Single Nucleotide - genetics / Protein Tyrosine Phosphatase, Non-Receptor Type 2 - antagonists & inhibitors / Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics / Protein Tyrosine Phosphatase, Non-Receptor Type 2 - metabolism / PTPN2 polymorphism / Real-Time Polymerase Chain Reaction / Reverse Transcriptase Polymerase Chain Reaction / RNA, Messenger - genetics / RNA, Small Interfering - genetics / Signal Transduction / T-Box Domain Proteins - genetics / T-Box Domain Proteins - metabolism