Abstract
T cell protein tyrosine phosphatase (TC-PTP / PTPN2) is an enzyme that is essential for the proper functioning of the immune system and that participates in the control of cell proliferation, and inflammation. We previously observed that TC-PTP−/− mice display various immunodeficiencies, hypersensitivity to LPS and die within three weeks of birth due to anemia and widespread inflammation. A recent analysis of the Wellcome Trust Case Control Consortium (WTCC) genome wide scan data, reported in 2007, indicated a potential role for TC-PTP in inflammatory bowel disease (IBD). To further investigate the potential role of TC-PTP in IBD, we studied heterozygous TC-PTP mutant mice challenged with dextran sulfate sodium (DSS) in their drinking water. In comparison to control animals, we observed significant changes in the colon mucosa of DSS-treated TC-PTP+/− mice, in the ratio of colon to body weight, as well as an up-regulation of mRNA transcripts for IL-6, IL-23, 1L-12β, IFN-γ, TNF-α. Moreover, up-regulation of serum IL-6 levels in DSS-treated TC-PTP+/− mice confirms that mice with a single copy of the TC-PTP gene display increased susceptibility to systemic inflammation due to bowel epithelial erosion resulting from DSS challenge. Our findings support the lack of modulation of Janus kinases 1 and 3 (Jak1, Jak3), and the downstream signal transducer and activator of transcription 1,3 and 5 (Stat1, Stat3, Stat 5) by PTPN2 in the development of IBD like condition. Pathological and molecular analysis reveal that the deficiency of TC-PTP results in pro-inflammatory condition in the bowel of heterozygous TC-PTP+/− mice. These novel findings in TC-PTP hemi-deficiency support the hypothesis that TC-PTP is an important regulator of inflammatory cytokine signaling and that it may be implicated in the pathophysiology of IBD.
Highlights
Ulcerative colitis and Crohn’s disease are the main two types of inflammatory bowel disease (IBD)
Crohn’s Disease, the 3rd ranking disease in a genome-wide association study performed by the Wellcome Trust Case Control Consortium (WTCC) in 2007 [2], was found associated with a SNP in a region of chromosome 18p11 with the only gene lying in this region being PTPN2, the encoding locus for the T-cell protein tyrosine phosphatase (TC-PTP) [2]
The Wellcome Trust Case Control Consortium and other groups identified SNPs associated with IBD in close proximity to the TC-PTP locus [1,2,3,4,5,6,7]
Summary
Ulcerative colitis and Crohn’s disease are the main two types of inflammatory bowel disease (IBD). The systemic inflammation in TC-PTP2/2 mice and various genetic studies focusing on the association of the PTPN2 locus with IBD led to the hypothesis that the absence of the enzymatic activity or decreased expression of TC-PTP may play a role in many chronic inflammatory conditions. We evaluated the role of TC-PTP as a modulator of inflammation in IBD relevant conditions in vivo, using a dextran sulfate sodium (DSS)-induced colitis mouse model. Heterozygosity of TC-PTP may prime the immune system to respond more readily to irritants such as DSS resulting in a more severe inflammatory condition This may partially explain the association of TC-PTP with chronic inflammatory diseases such as IBD [1,2,3,4,5,6,7]. TC-PTP is a key modulator in inflammation, and by detecting or controlling its expression or downstream events we may open new avenues in the diagnosis and treatments of inflammatory bowel diseases like colitis
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