Rat peritoneal mast cells release dipeptidyl peptidase II.
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ABSTRACT:
SUBMITTER: Struckhoff G
PROVIDER: S-EPMC1146808 | biostudies-other | 1986 May
REPOSITORIES: biostudies-other
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Project description:Peritoneal dialysis (PD) possesses multiple advantages for end stage renal disease. However, long-term PD triggers peritoneal fibrosis (PF). From the nationwide analysis of diabetic PD patients (n = 19,828), we identified the incidence of PD failure was significantly lower in diabetic patients treated with dipeptidyl peptidase 4 (DPP4) inhibitors. Experimental study further showed high concentration of glucose remarkably enhanced DPP4 to promote epithelial-mesenchymal transition (EMT) in the mesothelial cells. In chlorhexidine gluconate (CG)-induced PF model of rats, DPP4 expression was enriched at thickening peritoneum. Moreover, as to CG-induced PF model, DPP4 deficiency (F344/DuCrlCrlj strain), sitagliptin and exendin-4 treatments significantly inhibited DPP4 to reverse the EMT process, angiogenesis, oxidative stress, and inflammation, resulting in the protection from PF, preservation of peritoneum and the corresponding functional integrity. Furthermore, DPP4 activity was significantly correlated with peritoneal dysfunction. Taken together, DPP4 caused peritoneal dysfunction/PF, whereas inhibition of DPP4 protected the PD patients against PD failure.
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Project description:Dipeptidyl peptidase II (DPP II; EC 3.4.14.2) from rat kidney was purified to a specific activity of 65.4 micromol/min per mg of protein for Lys-Ala-beta-naphthylamide. The N-terminal and partial amino acid sequences of the enzyme were determined. The peptide sequences were used to identify expressed sequence tag (EST) clones. By using the cDNA fragment of one of the EST clones as a probe, we isolated a cDNA clone with 1710 bp encoding DPP II from a rat kidney cDNA library. The cDNA of rat DPP II contained an open reading frame of 1500 bp, coding for a protein of 500 amino acids. The first 10 residues of the purified enzyme matched the deduced protein sequence starting with residue 37, suggesting the presence of a signal peptide. The mature enzyme (464 residues) had a calculated molecular mass of 51400 Da, which was lower than the value (about 60000 Da) determined by SDS/PAGE; and the deduced amino acid sequence showed six potential N-glycosylation sites. The deduced amino acid sequence of rat DPP II shared high similarity with quiescent-cell proline dipeptidase (78% identity) and prolyl carboxypeptidase (38% identity) and bore the putative catalytic triad (Ser, Asp, His) conserved in serine peptidase families. We transiently transfected COS-7 cells with pcDNA3.1 containing the cloned cDNA and obtained the overexpression of an immunoreactive protein (of about 60000 Da). The transfected cells showed Lys-Ala-methylcoumarinamide-hydrolysing activity that was 50 times higher than the control cells.
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Project description:Exposure to mineral fibers is of substantial relevance to human health. A key event in exposure is the interaction with inflammatory cells and the subsequent generation of pro-inflammatory factors. Mast cells (MCs) have been shown to interact with titanium oxide (TiO₂) and asbestos fibers. In this study, we compared the response of rat peritoneal MCs challenged with the asbestos crocidolite and nanowires of TiO₂ to that induced by wollastonite employed as a control fiber. Rat peritoneal MCs (RPMCs), isolated from peritoneal lavage, were incubated in the presence of mineral fibers. The quantities of secreted enzymes were evaluated together with the activity of fiber-associated enzymes. The ultrastructural morphology of fiber-interacting RPMCs was analyzed with electron microscopy. Asbestos and TiO₂ stimulate MC secretion. Secreted enzymes bind to fibers and exhibit higher activity. TiO₂ and wollastonite bind and improve enzyme activity, but to a lesser degree than crocidolite. (1) Mineral fibers are able to stimulate the mast cell secretory process by both active (during membrane interaction) and/or passive (during membrane penetration) interaction; (2) fibers can be found to be associated with secreted enzymes-this process appears to create long-lasting pro-inflammatory environments and may represent the active contribution of MCs in maintaining the inflammatory process; (3) MCs and their enzymes should be considered as a therapeutic target in the pathogenesis of asbestos-induced lung inflammation; and (4) MCs can contribute to the inflammatory effect associated with selected engineered nanomaterials, such as TiO₂ nanoparticles.
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2011-12-31 | E-MTAB-583 | biostudies-arrayexpress
Project description:The presence of DPPII (dipeptidyl peptidase II; E.C. 3.4.14.2) has been demonstrated in various mammalian tissues. However, a profound molecular and catalytic characterization, including substrate selectivity, kinetics and pH-dependence, has not been conducted. In the present study, DPPII was purified from human seminal plasma to apparent homogeneity with a high yield (40%) purification scheme, including an inhibitor-based affinity chromatographic step. The inhibitor lysyl-piperidide (K(i) approximately 0.9 microM at pH 5.5) was chosen, as it provided a favourable affinity/recovery ratio. The human enzyme appeared as a 120 kDa homodimer. Mass spectrometric analysis after tryptic digestion together with a kinetic comparison indicate strongly its identity with QPP (quiescent cell proline dipeptidase), also called dipeptidyl peptidase 7. pH profiles of both kcat and kcat/K(m) clearly demonstrated that DPPII/QPP possesses an acidic and not a neutral optimum as was reported for QPP. Kinetic parameters of the human natural DPPII for dipeptide-derived chromogenic [pNA (p-nitroanilide)] and fluorogenic [4Me2NA (4-methoxy-2-naphthylamide)] substrates were determined under different assay conditions. DPPII preferred the chromogenic pNA-derived substrates over the fluorogenic 4Me2NA-derived substrates. Natural human DPPII showed high efficiency towards synthetic substrates containing proline at the P1 position and lysine at P2. The importance of the P1' group for P2 and P1 selectivity was revealed, explaining many discrepancies in the literature. Furthermore, substrate preferences of human DPPII and dipeptidyl peptidase IV were compared based on their selectivity constants (kcat/K(m)). Lys-Pro-pNA (k(cat)/K(m) 4.1x10(6) s(-1) x M(-1)) and Ala-Pro-pNA (kcat/K(m) 2.6x10(6) s(-1) x M(-1)) were found to be the most sensitive chromogenic substrates for human DPPII, but were less selective than Lys-Ala-pNA (kcat/K(m) 0.4x10(6) s(-1) x M(-1)).
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Project description:Dipeptidyl peptidase 4 (DPP-4) is a novel adipokine and may be involved in the association between adipose tissue and metabolic syndrome. We investigated DPP-4 and adiponectin levels in the serum, subcutaneous adipose tissue (SAT), and epicardial adipose tissue (EAT), and their relationship with preoperative factors, as well as comparing the DPP-4 levels in SAT and EAT with and without DPP-4 inhibitors. This study included 40 patients (25 men, age 67.5 ± 13.8 years). The serum adipokine, DPP-4, and adiponectin levels in SAT and EAT were measured using ELISA and Western blotting. The DPP-4 and adiponectin levels were significantly higher in the SAT than in the EAT. The serum DPP-4 and DPP-4 activity levels had no correlation with the DPP-4 levels in the SAT and EAT, but the DPP-4 levels in the SAT and EAT had a positive correlation. The DPP-4 levels in the SAT were positively correlated with atherosclerosis, diabetes mellitus, DPP-4-inhibitor use, and fasting blood glucose. The DPP-4 levels in the EAT showed a negative correlation with eGFR and a positive correlation with atrial fibrillation. The DPP-4 activity in the serum had a lower tendency in the group taking DPP-4 inhibitors than in the group not taking them. DPP-4 inhibitors may suppress angiogenesis and adipose-tissue hypertrophy.
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Project description:Human dipeptidyl peptidase I (DPPI) belongs to the family of papain-like cysteine peptidases. Its distinctive features are the unique exclusion domain which enables the eponymous activity and homotetramerization of DPPI, and its dependence on chloride ions for enzymatic activity. The oligomeric state of DPPI is unique in this family of predominantly monomeric peptidases. However, a distant DPPI ortholog from Plasmodium falciparum has been shown to be monomeric, indicating that the oligomeric state of DPPI varies between lineages. The aim of this work was to study the evolution of DPPI, with particular attention to the structural features that determine its characteristic enzymatic activity and preferences, and to reconstruct the evolution of its oligomerization. We analyzed fifty-seven selected sequences of DPPI and confirmed its presence in three lineages, namely, Amorphea (including animals and Amoebozoa), Alveolates and the metamonad Giardia. The amino acid residues that bind the chloride ion are highly conserved in all species, indicating that the dependence on chloride ions for activity is an evolutionarily conserved feature of DPPI. The number of N-glycosylation sites is significantly increased in animals, particularly vertebrates. Analysis of homology models and subunit contacts suggests that oligomerization is likely restricted to DPPIs in the Amorphea group.
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Project description:Controlling the overwhelming inflammatory reaction associated with polymicrobial sepsis remains a prevalent clinical challenge with few treatment options. In septic peritonitis, blood neutrophils and monocytes are rapidly recruited into the peritoneal cavity to control infection, but the role of resident sentinel cells during the early phase of infection is less clear. In particular, the influence of mast cells on other tissue-resident cells remains poorly understood. Here, we developed a mouse model that allows both visualization and conditional ablation of mast cells and basophils to investigate the role of mast cells in severe septic peritonitis. Specific depletion of mast cells led to increased survival rates in mice with acute sepsis. Furthermore, we determined that mast cells impair the phagocytic action of resident macrophages, thereby allowing local and systemic bacterial proliferation. Mast cells did not influence local recruitment of neutrophils and monocytes or the release of inflammatory cytokines. Phagocytosis inhibition by mast cells involved their ability to release prestored IL-4 within 15 minutes after bacterial encounter, and treatment with an IL-4-neutralizing antibody prevented this inhibitory effect and improved survival of septic mice. Our study uncovers a local crosstalk between mast cells and macrophages during the early phase of sepsis development that aggravates the outcome of severe bacterial infection.
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Project description:BACKGROUND AND PURPOSE: Current methods used to treat critical limb ischaemia (CLI) are hampered by a lack of effective strategies, therefore, therapeutic vasculogenesis may open up a new field for the treatment of CLI. In this study we investigated the ability of the DPP-4 inhibitor, sitagliptin, originally used as a hypoglycaemic agent, to induce vasculogenesis in vivo. EXPERIMENTAL APPROACH: Sitagliptin were administered daily to C57CL/B6 mice and eGFP transgenic mouse bone marrow-transplanted ICR mice that had undergone hindlimb ischaemic surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and circulating levels of endothelial progenitor cells (EPCs) respectively. Cell surface markers of EPCs and endothelial NOS (eNOS) in vessels were studied. KEY RESULTS: Sitagliptin elevated plasma glucagon-like peptide-1 (GLP-1) levels in mice subjected to ischaemia, decreased plasma dipeptidyl peptidase-4 (DPP-4) concentration, and augmented ischaemia-induced increases in stromal cell-derived factor-1 (SDF-1) in a dose-dependent manner. Blood flow in the ischaemic limb was significantly improved in mice treated with sitagliptin. Circulating levels of EPCs were also increased after sitagliptin treatment. Sitagliptin also enhanced the expression of CD 34 and eNOS in ischaemic muscle. In addition, sitagliptin promoted EPC mobilization and homing to ischaemic tissue in eGFP transgenic mouse bone marrow-transplanted ICR mice. CONCLUSION AND IMPLICATIONS: Circulating EPC levels and neovasculogenesis were augmented by the DPP-4 inhibitor, sitagliptin and this effect was dependent on an eNOS-related pathway in a mouse model of hindlimb ischaemia. The results indicate that oral administration of sitagliptin has therapeutic potential as an inducer of vasculogenesis.
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Project description:A synthetic basic decapeptide from the C4 domain of human immunoglobulin E, corticotropin-(1-24)-peptide, polyarginine and polylysine stimulated up to 90% net release of 5-hydroxytryptamine from mast cells in rat peritoneal-cell suspensions. Concentration-response curves to all four polypeptides were parallel. Polyarginine and polylysine (EC50 congruent to 0.05 microM) were approximately 100-fold more potent than immunoglobulin E decapeptide and corticotropin-(1-24)-peptide (EC50 congruent to 5 microM). Polypeptide-induced release was complete within 5-10s. Immunoglobulin-E-decapeptide-induced 5-hydroxytryptamine release was additive to that induced by low concentrations of polyarginine, but non-additive to that induced by high concentrations of polyarginine. In contrast, release induced by antigen was additive along the whole length of the concentration-response curve to polyarginine. Benzalkonium chloride inhibited immunoglobulin-E-decapeptide- and polyarginine-induced 5-hydroxytryptamine release but enhanced release induced by immunological stimulation.
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