Scharl, Michael and Mwinyi, Jessica and Fischbeck, Anne and Leucht, Katharina and Eloranta, Jyrki J. and Arikkat, Joba and Pesch, Theresa and Kellermeier, Silvia and Mair, Alma and Kullak-Ublick, Gerd A. and Truninger, Kaspar and Noreen, Faiza and Regula, Jaroslaw and Gaj, Pawel and Pittet, Valerie and Mueller, Christoph and Hofmann, Claudia and Fried, Michael and McCole, Declan F. and Rogler, Gerhard (2012) Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy. INFLAMMATORY BOWEL DISEASES, 18 (5). pp. 900-912. ISSN 1078-0998,
Full text not available from this repository. (Request a copy)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-? 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;)
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-TYROSINE-PHOSPHATASE; T-BET; HAPLOTYPE RECONSTRUCTION; TRANSCRIPTION FACTOR; ULCERATIVE-COLITIS; LINEAGE COMMITMENT; NOD2; CELLS; SUSCEPTIBILITY; GAMMA; Crohn's disease; NOD2; PTPN2 polymorphism; cytokine secretion |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 May 2020 06:54 |
| Last Modified: | 15 May 2020 06:54 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18836 |
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