We demonstrate that the secretome of mesenchymal stromal cells (MSCs) suppresses plasma cell (PC) immunoglobulin (Ig) production, induces plasmablast proliferation, and leads to interleukin-10-mediated blockade in vitro. We found that these effects are the result of MSCderived CC chemokine ligands CCL2 and CCL7. More specifically, MSCs further processed these CC chemokines by the activity of matrix metalloproteinases (MMPs), leading to the generation of proteolytically processed antagonistic CCL2 variant. Neutralizing CCL2 or inhibiting MMP enzymatic activity abolished the PCsuppressive effect of MSCs. We also observed that MMP-processed CCL2 suppresses signal transducer and activator of transcription 3 (STAT3) activation in PC. As a result, the transcription factor PAX5 is induced, thus explaining the inhibition of Ig synthesis.

The immune system requires for its proper ontogeny, differentiation, and maintenance the function of several tyrosine kinases and adapters that create and modify tyrosine phosphorylation sites. Tyrosine phosphorylation is a crucial protein modification in immune cell signaling and can be reversed by protein tyrosine phosphatases (PTPs). Much progress has been made in identifying and understanding PTP function in the immune system. In this review, we present one of these proteins, named T-cell PTPs (TC-PTP) (gene name PTPN2), a classical, non-receptor PTP that is ubiquitously expressed with particularly high expression in hematopoietic tissues. TC-PTP is remarkable not only by the fact that it appears to influence most, if not all, cells involved in the development of the immune system, from stem cells to differentiated lineages, but also recent findings have positioned it at the core of several human diseases from autoimmune disease to cancer.

PTP1B and T cell PTP (TC-PTP) are protein tyrosine phosphatases (PTPs) that share high sequence and structural homology yet play distinct physiological roles. While PTP1B plays a central role in metabolism and is an attractive drug target for obesity and type 2 diabetes, TC-PTP is necessary for the control of inflammation. In this review, we will discuss the growing evidence for the involvement of PTP1B in cancer, while proposing a role for TC-PTP in inflammation-induced tumorigenesis. Given the challenge of developing inhibitors specific for PTP1B alone, it is necessary to consider both enzymes and their roles in various cancer models.

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The T-cell protein tyrosine phosphatase (TC-PTP) is a negative regulator of the Jak/Stat cytokine signaling pathway. Our study shows that the absence of TC-PTP leads to an early bone marrow B-cell deficiency characterized by hindered transition from the pre-B cell to immature B-cell stage. This phenotype is intrinsic to the B cells but most importantly due to bone marrow stroma abnormalities. We found that bone marrow stromal cells from TC-PTP ؊ IntroductionThe T-cell protein tyrosine phosphatase (TC-PTP) is an intracellular enzyme encoded by Ptpn2. It is ubiquitously expressed, with highest levels in hematopoietic tissues (for a review, see Bourdeau et al 1 ). TC-PTP Ϫ/Ϫ mice appear physically normal until 10 to 14 days of age, at which time they progressively develop tissue mononuclear cell infiltrates. 2 Elevated levels of IFN-␥ can be measured at 19 days of age, 3 and the animals die between 21 and 35 days of age. TC-PTP Ϫ/Ϫ mice display defective hematopoiesis and immune function, characterized by anemia and splenomegaly secondary to sequestration of erythrocytes and accumulation of myeloid cells. 2 TC-PTP was also shown to interact with TRAF2 downstream of the TNF proinflammatory cytokine. This interaction inactivated Src and suppressed MAPK signaling. 4 TC-PTP has been identified as a critical regulator of colony-stimulating factor 1 (CSF-1) signaling and mononuclear phagocyte development. On CSF-1 stimulation, a deficiency in TC-PTP leads to enhanced tyrosine phosphorylation of the Grb2/Gab2/Shp2 complex by the CSF-1 receptor and increased activation of Erk. 5 These results identified TC-PTP as a key modulator of inflammatory signals as well as macrophage and lymphocyte functions.TC-PTP has been shown to control cytokine signaling events by its negative action on the Janus kinase (Jak) and signal transducer and activator of transcription (Stat) pathways (reviewed by Bourdeau et al 1 ). This cascade is crucial for hematopoietic development and cellular response to growth factors. 6 Using an in vitro approach, TC-PTP substrate-trapping mutant D/A was shown to interact with Jak1 and Jak3. 7 Stat1, Stat3, and Stat5a/5b were also identified as substrates for TC-PTP. [8][9][10] It is clear that TC-PTP is a key director of several cytokine-signaling pathways, and thus may be involved in the development of multiple hematopoietic lineages.Here, we report that bone marrow stromal cells from TC-PTP Ϫ/Ϫ mice secrete abnormally high levels of IFN-␥, resulting in constitutive phosphorylation of Stat1 in pre-B cells and altered B-cell development in the bone marrow. Our findings are novel and reflect the therapeutic potential of TC-PTP as a modulator of bone marrow stroma microenvironment that could be exploited in leukemia and other immune disorders. Materials and methods MiceGeneration of TC-PTP mutant mice was described previously. 2 Experiments were performed with mice on a mixed Balb/c-129SJ background and with mice backcrossed for 8 generation on Balb/c. All procedures were approved by the McGill University Rese...

Rheumatoid arthritis is an immune-mediated disease that primarily affects diarthrodial joints. Susceptibility and severity of this disease are influenced by nongenetic factors, such as environmental stress, suggesting an important role of epigenetic changes. In this review, we summarize the epigenetic changes (DNA methylation, histone modification and miRNA expression) in fibroblast-like synoviocytes, which are the joint-lining mesenchymal cells that play an important role in joint inflammation and damage. We also review the effects of these epigenetic changes on rheumatoid arthritis pathogenesis and discuss their therapeutic potential.

The control of tyrosine phosphorylation depends on the fine balance between kinase and phosphatase activities. Protein tyrosine phosphatase 1B (PTP-1B) and T cell protein tyrosine phosphatase (TC-PTP) are 2 closely related phosphatases known to control cytokine signaling. We studied the functional redundancy of PTP-1B and TC-PTP by deleting 1 or both copies of these genes by interbreeding TC-PTP and PTP-1B parental lines. Our results indicate that the double mutant (tcptp ؊/؊ ptp1b ؊/؊ ) is lethal at day E9. immune system ͉ interferon gamma ͉ lymphocyte development ͉ protein tyrosine phosphatase T cell protein tyrosine phosphatase (TC-PTP; also known as PTPN2) and protein tyrosine phosphatase 1B (PTP-1B; also known as PTPN1) are intracellular phosphatases with a high degree of sequence and structural homology within the catalytic domain (1, 2). PTP-1B is known to dephosphorylate the insulin receptor (3, 4), and ptp1b Ϫ/Ϫ mice are protected from dietinduced insulin-resistance and obesity (3,5,6). This phenotype has incited much interest in PTP-1B inhibitors in treating type II diabetes (7,8). However, because of the structural homology with TC-PTP, none of the small-molecule inhibitors developed to date exhibits a high degree of selectivity against PTP-1B, and only a few are currently in clinical trials.Both TC-PTP and PTP-1B have been shown to modulate cytokine receptor signaling (reviewed in ref. 9), including IFN-␥ signaling (10, 11). IFN-␥ is a major inflammatory cytokine, and ligation of the IFN-␥ receptor results in the activation of cytoplasmic Jak1 and Jak2 kinases as well as the transcription factor Stat1 (12). Jak1 and Stat1 are known substrates of TC-PTP (11, 13), whereas Jak2 is known to be dephosphorylated by PTP-1B (10). Consequently, we hypothesized that the deletion of both TC-PTP and PTP-1B would exacerbate the inflammatory phenotype seen in tcptp Ϫ/Ϫ mice (14, 15).The data presented here indicate that at least 1 copy of tcptp or ptp1b is required for normal embryonic development. Our results show that the sequential ablation of TC-PTP and PTP-1B reveals a thus-far undetected gene dosage effect. This suggests that small-molecule inhibitors against PTP-1B that also inhibit TC-PTP may have multilevel effects that are proportional to the net reduction in both TC-PTP and PTP-1B activity.

Despite the availability of several therapies for rheumatoid arthritis (RA) that target the immune system, a large number of RA patients fail to achieve remission. Joint-lining cells, called fibroblast-like synoviocytes (FLS), become activated during RA and mediate joint inflammation and destruction of cartilage and bone. We identify RPTPσ, a transmembrane tyrosine phosphatase, as a therapeutic target for FLS-directed therapy. RPTPσ is reciprocally regulated by interactions with chondroitin sulfate or heparan sulfate containing extracellular proteoglycans in a mechanism called the proteoglycan switch. We show that the proteoglycan switch regulates FLS function. Incubation of FLS with a proteoglycan-binding RPTPσ decoy protein inhibited cell invasiveness and attachment to cartilage by disrupting a constitutive interaction between RPTPσ and the heparan sulfate proteoglycan syndecan-4. RPTPσ mediated the effect of proteoglycans on FLS signaling by regulating the phosphorylation and cytoskeletal localization of ezrin. Furthermore, administration of the RPTPσ decoy protein ameliorated in vivo human FLS invasiveness and arthritis severity in the K/BxN serum transfer model of RA. Our data demonstrate that FLS are regulated by an RPTPσ-dependent proteoglycan switch in vivo, which can be targeted for RA therapy. We envision that therapies targeting the proteoglycan switch or its intracellular pathway in FLS could be effective as a monotherapy or in combination with currently available immune-targeted agents to improve control of disease activity in RA patients.