Increased susceptibility to dextran sulfate sodium induced colitis in the T cell protein tyrosine phosphatase heterozygous mouse.
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-12beta, IFN-gamma, TNF-alpha. 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.
Hassan
Syed-Wajahat
SW
Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Canada.
Doody
Karen M
KM
Hardy
Serge
S
Uetani
Noriko
N
Cournoyer
Denis
D
Tremblay
Michel L
ML
D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000473:pathology; D016207:Cytokines / Q000097:blood / Q000235:genetics; D017931:DNA Primers; D016264:Dextran Sulfate / Q000633:toxicity*; D006579:Heterozygote; D018836:Inflammation Mediators / Q000097:blood; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D015431:Weight Loss
D016207:Cytokines; D017931:DNA Primers; D018836:Inflammation Mediators; D016264:Dextran Sulfate; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2