Role of dipeptidyl peptidase IV (DP IV)-like enzymes in T lymphocyte activation: investigations in DP IV/CD26-knockout mice

Reinhold, Dirk; Goihl, Alexander; Wrenger, Sabine; Reinhold, Annegret; Kühlmann, Ulrike C.; Faust, Jürgen; Neubert, Klaus; Thielitz, Anja; Brocke, Stefan; Täger, Michael; Ansorge, Siegfried; Bank, Ute

doi:10.1515/cclm.2009.062

Cited by 63 publications

(55 citation statements)

References 27 publications

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“…An inhibitor of DPP8 and DPP9 attenuates proliferation in in vitro models of human T-cell activation [23] . An inhibitor selective for DPP8 and DPP9 vs related proteases can suppress DNA synthesis in mitogenstimulated splenocytes from both wildtype DPP4 + / + and DPP4 -/ -gene knockout (gko) mice [27] . Moreover, DPP8 and DPP9 have been implicated in hematopoiesis and in inflammatory diseases including arthritis [2,28,29] .…”

Section: Introductionmentioning

confidence: 99%

Regulation of dipeptidyl peptidase 8 and 9 expression in activated lymphocytes and injured liver

Chowdhury

Chen²,

Yao³

et al. 2013

WJG

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), human lymphoma cell lines and mouse splenocytes stimulated with pokeweed mitogen (PWM) or lipopolysaccharide (LPS), and in dithiothreitol (DTT) and mitomycin-C treated Raji cells. DPP8 and DPP9 expression were measured in epidermal growth factor (EGF) treated Huh7 hepatoma cells, in fibrotic liver samples from mice treated with carbon tetrachloride (CCl4) and from multidrug resistance gene 2 (Mdr2 /Abcb4 ) gene knockout (gko) mice with biliary fibrosis, and in human end stage primary biliary cirrhosis (PBC). RESULTS:All three lymphocyte subsets expressed DPP8 and DPP9 mRNA. DPP8 and DPP9 expression were upregulated in both PWM and LPS stimulated mouse splenocytes and in both Jurkat T-and Raji B-cell lines. DPP8 and DPP9 were downregulated in DTT treated and upregulated in mitomycin-C treated Raji cells. DPP9-transfected Raji cells exhibited more annexin V + cells and associated apoptosis. DPP8 and DPP9 mRNA were upregulated in CCl4 induced fibrotic livers but not in the lymphocytes isolated from such livers, while DPP9 was upregulated in EGF stimulated Huh7 cells. In contrast, intrahepatic DPP8 and DPP9 mRNA expression levels were low in the Mdr2 gko mouse and in human PBC compared to non-diseased livers. CONCLUSION:These expression patterns point to biological roles for DPP8 and DPP9 in lymphocyte activation and apoptosis and in hepatocytes during liver disease pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Regulation of dipeptidyl peptidase 8 and 9 expression in activated lymphocytes and injured liver

Chowdhury

Chen²,

Yao³

et al. 2013

WJG

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“…hDPPIV regulates various physiological processes including immune system, endocrine functions, central nervous system, gastrointestinal system, inflammation, rheumatoid arthritis and cell adhesion. The enzyme removes dipeptides from N-terminus of regulatory peptides such as chemokines, neuropeptides and peptide hormones (Reichelt et al 1981;Shattock et al 1990; Urade et al 2006;Iwaki-Egawa et al 1998;Mentlein 1999;Brudnak 2001;Brudnak et al 2002;Langford 2003;Lambeir et al 2002;Reichelt and Knivsberg 2003;Aertgeerts et al 2004;Reinhold et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Monitoring of the effects of transfection with baculovirus on Sf9 cell line and expression of human dipeptidyl peptidase IV

et al. 2013

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Human dipeptidylpeptidase IV (hDPPIV) is an enzyme that is in hydrolase class and has various roles in different parts of human body. Its deficiency may cause some disorders in the gastrointestinal, neurologic, endocrinological and immunological systems of humans. In the present study, hDPPIV enzyme was expressed on Spodoptera frugiperda (Sf9) cell lines as a host cell, and the expression of hDPPIV was obtained by a baculoviral expression system. The enzyme production, optimum multiplicity of infection, optimum transfection time, infected and uninfected cell size and cell behavior during transfection were also determined. For maximum hDPPIV (269 mU mL -1 ) enzyme, optimum multiplicity of infection (MOI) and time were 0.1 and 72 h, respectively. The size of infected cells increased significantly (P \ 0.001) after 24 h post infection. The results indicated that Sf9 cell line was applicable to the large scale for hDPPIV expression by using optimized parameters (infection time and MOI) because of its high productivity (4.03 mU m L -1 h -1 ).

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“…Interestingly, a DPP8/DPP9 selective inhibitor, (2S,3R)-2-(2-amino-3-methyl-1-oxopentan-1-yl)-1,3-dihydro-2H-isoindole hydrochloride, attenuates lymphocyte proliferation (14,15). Recently, the antigenic peptide RUI [34][35][36][37][38][39][40][41][42] has been identified as a natural DPP9 substrate, indicating a potential role of DPP9 in cytoplasmic peptide degradation for antigen presentation (16).…”

Section: Introductionmentioning

confidence: 99%

A Novel Role of Dipeptidyl Peptidase 9 in Epidermal Growth Factor Signaling

Yao

Kim

et al. 2011

Molecular Cancer Research

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Dipeptidyl peptidase IV (DPP4), DPP8, DPP9, and fibroblast activation protein (FAP), the four proteases of the DPP4 gene family, have unique peptidase and extra-enzymatic activities that have been implicated in various diseases including cancers. We report here a novel role of DPP9 in regulating cell survival and proliferation through modulating molecular signaling cascades. Akt (protein kinase B) activation was significantly inhibited by human DPP9 overexpression in human hepatoma cells (HepG2 and Huh7) and human embryonic kidney cells (HEK293T), whereas extracellular signal-regulated kinases (ERK1/2) activity was unaffected, revealing a pathwayspecific effect. Interestingly, the inhibitory effect of DPP9 on Akt pathway activation was growth factor dependent. DPP9 overexpression caused apoptosis and significantly less epidermal growth factor (EGF)-mediated Akt activation in HepG2 cells. However, such inhibitory effect was not observed in cells stimulated with other growth factors, including connective tissue growth factor, hepatic growth factor, insulin or platelet-derived growth factor-BB. The effect of DPP9 on Akt did not occur when DPP9 enzyme activity was ablated by either mutagenesis or inhibition. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a major downstream effector of Ras. We found that DPP9 and DPP8, but not DPP4 or FAP, associate with H-Ras, a key signal molecule of the EGF receptor signaling pathway. These findings suggest an important signaling role of DPP9 in the regulation of survival and proliferation pathways. Mol Cancer Res; 9(7); 948-59. Ó2011 AACR.

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Role of dipeptidyl peptidase IV (DP IV)-like enzymes in T lymphocyte activation: investigations in DP IV/CD26-knockout mice

Abstract: Our data support the hypothesis that DP8 and/or DP9 represent additional pharmacological targets for the suppression of T cell proliferation and for anti-inflammatory therapy.

Cited by 63 publications

References 27 publications

Regulation of dipeptidyl peptidase 8 and 9 expression in activated lymphocytes and injured liver

Regulation of dipeptidyl peptidase 8 and 9 expression in activated lymphocytes and injured liver

Monitoring of the effects of transfection with baculovirus on Sf9 cell line and expression of human dipeptidyl peptidase IV

A Novel Role of Dipeptidyl Peptidase 9 in Epidermal Growth Factor Signaling

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