Loss of T-cell protein tyrosine phosphatase in the intestinal epithelium promotes local inflammation by increasing colonic stem cell proliferation.

T-cell protein tyrosine phosphatase (TC-PTP) has a critical role in the development of the immune system and has been identified as a negative regulator of inflammation. Single-nucleotide polymorphisms in the TC-PTP locus have been associated with increased susceptibility to inflammatory bowel diseases (IBDs) in patients. To further understand how TC-PTP is related to IBDs, we investigated the role of TC-PTP in maintaining the intestinal epithelial barrier using an in vivo genetic approach. Intestinal epithelial cell (IEC)-specific deletion of TC-PTP was achieved in a mouse model at steady state and in the context of dextran sulphate sodium (DSS)-induced colitis. Knockout (KO) of TC-PTP in IECs did not result in an altered intestinal barrier. However, upon DSS treatment, IEC-specific TC-PTP KO mice displayed a more severe colitis phenotype with a corresponding increase in the immune response and inflammatory cytokine profile. The absence of TC-PTP caused an altered turnover of IECs, which is further explained by the role of the tyrosine phosphatase in colonic stem cell (CoSC) proliferation. Our results suggest a novel role for TC-PTP in regulating the homeostasis of CoSC proliferation. This supports the protective function of TC-PTP against IBDs, independently of its previously demonstrated role in intestinal immunity.

Characterization of PTPN2 and its use as a biomarker.

For years, the two main isoforms of PTPN2 have been an interesting yet academic topic of debate for researchers working on this phosphatase. In recent years, several studies were published in which these isoforms were attributed specific functions. Most importantly, differences in their stoichiometry have been reported to be associated with certain diseases such as inflammatory bowel diseases (IBDs). Hence, understanding the evolutionary ontogeny of the main transcripts and the physiological consequences of their expression have now become clinically relevant issues. Herein we describe the genomic controls placed upon PTPN2, the identified splice variants, the encoded PTPN2 proteins, and both the known and putative post-translational modifications that have been reported. Moreover, we examine the expression of PTPN2 isoforms in specific tissues as well as in a disease setting. PTPN2 is an important negative regulator of inflammation. Therefore, the following protocols are effective approaches for its adequate monitoring in inflammatory diseases' progression and outcome.

T cell protein tyrosine phosphatase deficiency results in spontaneous synovitis and subchondral bone resorption in mice.

OBJECTIVE: T cell protein tyrosine phosphatase (TC-PTP) is an important regulator of hematopoiesis and cytokine signaling. Recently, several genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) in the locus of TC-PTP that are associated with rheumatoid arthritis and juvenile idiopathic arthritis, among other autoimmune diseases. The aim of this study was to evaluate the effect of TC-PTP deficiency on the bone and joint environment using a knockout mouse model. METHODS: Radiographic and micro-computed tomography analyses were performed on femurs of 3-week-old mice. In addition, the femorotibial joints were assessed by histology, flow cytometry, and cytokine detection. RESULTS: Deficiency of TC-PTP resulted in decreased bone volume as well as an increase in osteoclast density within the mouse femurs. In addition, synovitis, characterized by infiltration of mixed inflammatory cell types and proinflammatory cytokines, developed in the knee joints of TC-PTP(-/-) mice. CONCLUSION: These findings demonstrate that loss of TC-PTP expression results in synovitis with several hallmarks of inflammatory arthritis. The inflammatory environment observed in the knee joints of TC-PTP(-/-) mice differs from the systemic inflammation previously described in these mice and merits further research into the role of TC-PTP in the synovium. Furthermore, the results support recently described associations between SNPs in the TC-PTP locus and arthritis incidence.