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

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...

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Veröffentlicht in:Inflammatory bowel diseases 2012-05, Vol.18 (5), p.900-912
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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.
ISSN:1078-0998
1536-4844
DOI:10.1002/ibd.21913