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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-52588

Scharl, M; Mwinyi, J; Fischbeck, A; Leucht, K; Eloranta, J J; Arikkat, J; Pesch, T; Kellermeier, S; Mair, A; Kullak-Ublick, G A; Truninger, K; Noreen, F; Regula, J; Gaj, P; Pittet, V; Mueller, C; Hofmann, C; Fried, M; McCole, D F; Rogler, G (2012). Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy. Inflammatory Bowel Diseases, 18(5):900-912.

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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. (Inflamm Bowel Dis 2011;).

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Gastroenterology and Hepatology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2012
Deposited On:16 Dec 2011 12:32
Last Modified:14 Dec 2013 05:50
Publisher:Wiley-Blackwell
ISSN:1078-0998
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1002/ibd.21913
PubMed ID:22021207
Citations:Web of Science®. Times Cited: 13
Google Scholar™
Scopus®. Citation Count: 16

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