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PubMed1986

A novel dipeptidyl peptidase II from the porcine ovary. Purification and characterization of a lysosomal serine protease showing enhanced specificity for prolyl bonds.

A variant form of dipeptidyl peptidase II (DPP II), initially reported under the name of "DPP V" (Eisenhauer, D. A., and McDonald, J. K. (1982) Fed. Proc. 41, 507), was detected in aqueous extracts of porcine ovaries on the basis of a markedly enhanced action on prolyl bonds. This porcine form of DPP II, which was most sensitively assayed on Phe-Pro-2-naphthylamide (Phe-Pro-NNap), was purified 1400-fold to a specific activity of 28 mumol/min/mg of protein (pH 6.0, 37 degrees C) from an aqueous extract of hog ovaries taken during pregnancy, when ovarian levels of DPP II are some 3- to 8-fold higher. Purification involved ammonium sulfate fractionation, molecular exclusion chromatography, chromatofocusing, affinity chromatography on concanavalin A-Sepharose 4B, and high performance ion exchange chromatography. The purified enzyme, which was apparently electrophoretically homogeneous at pH 3, 7, and 8.8 (pI = 5.0), was shown to be an Mr = 110,000 glycoprotein containing about 2% carbohydrate (primarily mannose) and less than 1% sialic acid, and to consist of two noncovalently linked Mr = 54,000 subunits. A serine catalytic mechanism was supported by inhibitor studies and by common mobilities seen during electrophoresis for (histochemically detected) Phe-Pro-arylamidase activity and the [14C]diisopropyl fluorophosphate-labeled enzyme. In the standard fluorometric assay at 37 degrees C, Phe-Pro-NNap (0.2 mM) was hydrolyzed optimally at pH 6.0 (Km = 45 microM; kcat = 54 s-1). In comparison to the rate seen on Lys-Ala-NNap, the usual DI P II assay substrate, rates seen on Phe-Pro-, Lys-Pro-, and Arg-Pro-NNap were about 8-, 4-, and 2-fold higher, respectively. No action occurred on N-blocked derivatives or on Pro-NNap. Action on oligopeptides appeared to be limited to tripeptides, in particular those containing proline or alanine in the P1 position, i.e. Phe-Pro-Ala (100%), Lys-Ala-Ala (35%), Ala-Ala-Ala (33%), and Gly-Pro-Ala (26%). Only a trace of activity was seen on Phe-Pro-Ala-Ala, and none on Z-Phe-Pro-Ala or Ala-Ala-Ala-OMe. Evidence for the lysosomal localization of DPP II included sedimentability and latency and its distribution, coincident with acid phosphatase, in two distinct isopycnic regions following equilibrium density centrifugation. Lysosomal heterogeneity was suggested by this dual isopycnic banding.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1984

[Peptidases in the kidney of male rats following castration and testosterone substitution].

The localization of aminopeptidase M (APM), dipeptidyl peptidase I (DAP I), II (DAP II) and IV (DAP IV) in the renal section was investigated histochemically, and their activities were determined fluorometrically in renal homogenate of normal, castrated and testosteron treated male rats.--After castration the activities of the lysosomal DAP II (pars convoluta of the proximal tubule), DAP I (distal and proximal tubule) and of the mainly membrane-bound DAP IV (glomeruli, brush border of the proximal tubule) increase in comparison to normal males, whereas the activities of the brush border-bound APM decrease. After testosteron treatment of castrated animals (0.1, 0.5 and 1.0 mg testosterone proprionate/100 g BW and day; 5-day treatment) the activities of DAP I, II and IV decrease again, so that after treatment with 0.1 mg testosterone proprionate, the activities of DAP I and II approach those in normal males.--The additionally determined urinary protein excretion shows that there is a significant decrease in proteinuria after castration, whereas testosterone treatment of castrated animals is accompanied by an increase of proteinuria.--Our results would suggest that the protein catabolism in the proximal tubule and the proteinuria are interrelated, and that testosterone influences (decreases) the protein catabolism in the proximal tubule. This means that high activities of lysosomal proteinases in the proximal tubule (castrates) are accompanied by a low proteinuria, and low activities of those proteinases (testosterone treated castrated or normal males) by a high proteinuria.

Aminopeptidases↗
PubMed1980

[Structure-activity relationship in the enzymatic hydrolysis of dipeptide aryl amides by dipeptidyl peptidase IV].

Quantitative structure activity analysis of the substrate types Ala-Ala-AR and Ala-Pro-AR containing different substituents in the aryl ring showed that the rate-limiting step in the hydrolysis of the alanine substrates by dipeptidyl peptidase IV occurs in th acylation reaction (kcat approximately k2). Probably, the tetrahedral intermediate of the acylation process has a real life time. The positive q-value of the Hammett-equation in k'cat suggests that the N-atom of the arylamide is charged more negatively in the transition state TI not equal to than in the original state TI. The analysis of the quantitative conformation activity relationship (QCAR) gives information on the steric situation in the tetrahedral intermediate of the acylation step near the transition state. The rate limiting step in the hydrolysis of the substrates of the proline type occurs in the deacylation reaction.

Dipeptides↗
PubMed1981

Brain peptidase with a unique neuronal localization: the histochemical distribution of dipeptidyl-aminopeptidase II.

To assess whether specific peptidases regulate neuropeptide disposition, we have examined histochemically the localization of dipeptidyl-aminopeptidase II (DAP II). With beta-naphthylamide (beta-NA) substrates, this enzyme has a selectivity for lysyl-alanyl-beta-NA. DAP II staining is highly localized to specific neuronal populations with no staining over glia. Areas in the brain with high densities of DAP II staining include the mitral cells in the olfactory bulb, polymorphic cells in the hippocampus, the paraventricular nucleus of the hypothalamus, and the anterior dorsal thalamus, Purkinje cells, and deep nuclei in the cerebellum. Staining occurs in virtually all cell groups in the inferior colliculus, red nucleus, oculomotor nucleus, and mesencephalic nucleus of the trigeminal nerve, the stratum album of the superior colliculus, as well as most cells in the cochlear and superior olivary nuclei. DAP II localizations do not correlate fully with those on any known neuropeptide. Of the numerous peptides evaluated, only glucagon competes substantially for the DAP Ii substrate, reducing enzymatic activity by 50% at a 2 x 10(-5) M concentration.

Animals↗
PubMed1995

Expression of recombinant human granzyme B. A processing and activation role for dipeptidyl peptidase I.

Human granzyme B (hGrzB) is the key member of a family of granule serine proteases (granzymes) that participate in target cell death inflicted by cytotoxic lymphocytes. The proenzyme activation peptide predicted from the cDNA encoding hGrzB is composed of two residues. We have devised a PCR strategy to delete this activation dipeptide within hGrzB and express active recombinant hGrzB in mammalian COS cells. Lysates of COS cells transfected with modified hGrzB cDNA were able to hydrolyze tert-butyloxycarbonyl-Ala-Ala-Asp-thiobenzyl ester (Boc-Ala-Ala-Asp-SBzl), whereas lysates transfected with unmodified hGrzB cDNA were inactive. Accordingly, active recombinant hGrzB displayed no significant activities toward substrates containing Met-, Lys-, or Phe- at P1. It has been suggested that the mechanism by which the amino-terminal dipeptide is normally cleaved to generate active GrzB involves dipeptidyl peptidase I (DPPI). Our studies demonstrated that lysates of COS cells cotransfected with unmodified hGrzB cDNA (inactive) and rat DPPI cDNA were able to hydrolyze Boc-Ala-Ala-Asp-SBzl. Similarly, lysates of COS cells transfected with unmodified hGrzB cDNA, and devoid of Asp-ase activity, were also activated upon the addition of bovine spleen DPPI in a pH and time-dependent fashion. These results suggest that the activation dipeptide, and more particularly DPPI, may play and important role in the normal post-translational processing and activation of hGrzB in cytotoxic lymphocytes.

Animals↗
PubMed1993

Increased excretion of proline-containing peptides in dipeptidyl peptidase IV-deficient rats.

We have reported that a substrain of Fischer 344 rat exhibits a deficiency of dipeptidyl peptidase IV (Watanabe et al. Experientia 43: 400-401, 1987). In this study, this rat model was found to excrete large amounts of proline-containing peptides in the urine. The peptide fraction also contained other amino acids, such as hydroxyproline and glycine. The results indicate that the enzyme might be involved in the metabolism of collagens and related peptides.

Animals↗
PubMed1993

Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I.

The proenzyme activation peptides predicted from cDNAs encoding each of the granule serine proteases synthesized by cytotoxic lymphocytes and myeloid and mast cells are composed of 2 residues. The mechanism by which these amino-terminal dipeptides are cleaved to generate the active enzymes has not been elucidated. The comparable distribution of dipeptidyl peptidase I (DPPI) and serine proteases and the ability of DPPI to hydrolyze relevant dipeptide sequences suggested a role for DPPI in the processing and activation of granule serine proteases. This study demonstrates that inhibition of DPPI activity is associated with impairment of the generation of granule serine protease activity in CD8(+) T cells, lymphokine-activated killer cells, P815 mastocytoma cells, and U-937 myeloid cells. Inhibition of DPPI resulted in impairment of the generation of cathepsin G enzymatic activity without reduction in the amount of immunoreactive cathepsin G produced. In U-937 cells pulsed with [3H]isoleucine, inhibition of DPPI activity was associated with the accumulation of the inactive proenzyme form of cathepsin G bearing an amino-terminal dipeptide extension to the isoleucine residue that normally occupies the amino terminus of the enzymatically active protein. These results indicate that DPPI plays a requisite role in the post-translational processing and activation of members of the family of granule serine proteases expressed in bone marrow-derived effector cells.

Amino Acid Sequence↗
PubMed1993

Dipeptidyl peptidase I is enriched in granules of in vitro- and in vivo-activated cytotoxic T lymphocytes.

Recent studies have suggested that dipeptidyl peptidase I (DPPI) is the major post-translational processing enzyme responsible for generating activated myeloid and lymphoid granule serine proteases. The current studies assessed the relative levels of DPPI and granzyme A (BLT esterase) in B6 anti-H-2d-specific CTL generated in mixed lymphocyte cultures (in vitro-activated CTL), by infusion of B6 spleen cells into irradiated H-2d mice (graft-vs-host, GVH CTL) or by 1 degree and 2 degrees peritoneal immunization of B6 mice with P815 (H-2d) cells (PE CTL). In contrast to low levels of DPPI activity in unstimulated CD4+ spleen T cells, both unstimulated CD8+ spleen T cells and in vitro-activated CTL populations were several-fold enriched in DPPI activity, while PE CTL and GVH CTL expressed even higher levels of DPPI. Depletion of DPPI-enriched cells by treatment with Leu-Leu-OMe resulted in loss of cytolytic effector function from each CTL population. However, PE CTL and GVH CTL were more sensitive to the toxicity of Leu-Leu-OMe than were in vitro-activated CTL. While standard BLT esterase assays detected much higher levels of this serine protease activity in GVH CTL or in vitro-activated CTL than in PE CTL, levels of BLT esterase activity significantly above the basal levels present in unstimulated CD8+ or CD4+ T lymphocytes were found in association with immunoreactive granzyme A in lysates of PE CTL. In both PE CTL and in vitro-activated CTL, DPPI and BLT esterase activity co-localized in the granule fraction of cell lysates, and similar percentages of total cellular BLT esterase and DPPI were exocytosed upon cross-linking of surface CD3. Thus, both in vivo- and in vitro-activated CTL were found to possess functional granules containing readily detectable albeit somewhat different levels of DPPI and granzyme A activity.

Animals↗
PubMed1997

A selective inhibitor of dipeptidyl peptidase I impairs generation of CD8+ T cell cytotoxic effector function.

CTL express high levels of dipeptidyl peptidase I (DPPI), a granule thiol protease able to convert the zymogen precursors of granzymes A and B into active proteases. In the present studies, the effects of specific inhibition of DPPI on generation of CTL effector functions were examined. When T cell DPPI activity was inhibited by >95% throughout 5-day MLC, a significant reduction in the generation of CD8+ T cell BLT esterase activity (<30% of control) and cytolytic activity (<10% of control) was observed. DPPI inhibition during the second to fourth days of 5-day MLC also was associated with reduced proliferation of CD8+ T cells, but had no effect on CD4+ T cell proliferation or IL-2 production by either population. CTL generated in the continuous presence of DPPI inhibition also exhibited impaired lysis of anuclear erythrocyte targets and diminished killing of nucleated targets by perforin-independent pathways. In contrast, inhibition of DPPI during only the last 24 h of 5-day MLC was associated only with reduced generation of BLT esterase activity and reduced lysis of nucleated targets by perforin-dependent pathways. Repeated or delayed inhibition of DPPI in MLC containing granzyme B-deficient responder cells also impaired generation of cytotoxic activity. These results indicate that DPPI or other DPPI-like protease activities not only are required for the activation of granzymes, but also play a role in the expansion and differentiation of full CD8+ T cell cytolytic activity.

Animals↗
PubMed1998

Dipeptidyl peptidase I and granzyme A are coordinately expressed during CD8+ T cell development and differentiation.

Dipeptidyl peptidase I (DPPI) is a granule protease that plays a requisite role in processing the proenzyme form of the CTL granule serine proteases (granzymes). This study assesses DPPI mRNA and enzyme expression during T lymphocyte ontogeny and CTL differentiation. The most immature CD3- CD4- CD8- thymocytes were found to express >40-fold higher levels of DPPI mRNA, although levels of DPPI enzymatic activity in CD3- CD4- CD8- thymocytes were only modestly higher than those seen for CD4+ CD8+ or CD4+ CD8- thymocytes. More mature CD8+ CD4- thymocytes and CD8+ splenocytes expressed significantly higher levels of DPPI mRNA and enzymatic activity than CD4+ CD8+ or CD4+ CD8- thymocytes. Granzyme A mRNA expression was observed in DPPI expressing CD3- CD4- CD8- and CD8+ CD4- thymocytes and was also observed in CD8+ CD4- splenocytes; however, expression was not observed in CD4+ CD8+ or CD4+ CD8- thymocytes. Both DPPI mRNA and granzyme A mRNA expression in CD8+ T cells decreased to very low or undetectable levels during the first 48 h after allostimulation in MLCs. However, peak levels of both DPPI and granzyme A expression were observed later in the course of CD8+ T cell responses to alloantigen, with DPPI mRNA expression peaking on either day 3 or day 4 and granzyme A expression peaking at the end of a 5-day MLR. These data indicate that DPPI is expressed at all stages of T cell ontogeny and differentiation in which granzyme A mRNA is detected; consequently, DPPI appears to be available for the processing and activation of granzyme A during both CD8+ T cell development and differentiation.

Animals↗
PubMed1999

Identification of dipeptidyl peptidase IV as the antigen of a monoclonal anti-prostasome antibody.

BACKGROUND: Our purpose was to elucidate the identity of an antigen of a monoclonal antibody against prostasomes, which are prostate-derived organelles occurring freely in human semen. METHODS: Monoclonal antibodies against prostasomes were generated by intrasplenic immunization to allow better characterization of the prostasomes. One third of the resulting antibodies bound to a 110-kDa prostasomal protein on Western blots. RESULTS: The antigen was purified from seminal prostasomes by anion exchange chromatography and gel electrophoresis. After in-gel digestion and amino-acid sequence analysis of selected peptides, it was identified as dipeptidyl peptidase IV (DPP IV), EC 3.4.14.5, also known as T-cell-activating antigen CD26. No DPP IV could be detected in the supernatant obtained after preparative ultracentrifugation of the prostasomes. CONCLUSIONS: DPP IV/CD26 is structurally bound to prostasomes rather than being free in seminal fluid. This enzyme may play a critical role in the promoting effect of prostasomes on forward motility of spermatozoa.

Amino Acid Sequence↗
PubMed1996

Cytofluorographic evidence that thymocyte dipeptidyl peptidase IV (CD26) activity is altered with stage of ontogeny and apoptotic status.

CD26 is a multifunctional molecule implied to have a variety of roles in the immune response including its activity as a membrane exopeptidase (Dipeptidyl peptidase IV) which cleaves several protein molecules. In order to further define the expression and functional activity of CD26 in the developing thymus, we utilized a nondisruptive, cytofluorogenic assay which allowed simultaneous measurement of DPP IV activity with a fluorochrome-conjugated peptide substrate and surface staining of the T lymphocyte lineage antigens CD4 and CD8. Neonatal and adult murine thymi were examined using the three-color assay and significant differences in DPP IV activity were found among the thymocyte subsets defined by their CD4/CD8 phenotype. Single-positive cells bore higher activity than CD4-/CD8- cells and neonates had higher activity than adults. Thymocytes with characteristics consistent with apoptotic cells expressed higher DPP IV activity. Thus, DPP IV appears to be upregulated both as thymocytes mature and among thymocytes which are undergoing programmed cell death. These results suggest that CD26 is ontogenically controlled during T cell maturation and may play a role in thymic deletion of emerging clones.

Amino Acid Sequence↗
PubMed1998

CD26 expression and dipeptidyl peptidase IV activity in an aggressive hepatosplenic T-cell lymphoma.

The transmembrane serine aminopeptidase dipeptidyl peptidase IV (DPP IV) (also known as CD26) participates in several immunological functions and has a binding affinity for several molecules, including collagen, which may be an integral mechanism for T cells to traverse endothelial barriers. Since CD26 is phenotypically expressed in certain T-cell malignancies, this study utilized a novel four-color cytofluorographic procedure to measure DPP IV enzymatic activity concurrently with the expression of other surface markers in an aggressive hepatosplenic T-cell lymphoma. Immunophenotypic analysis by flow cytometry revealed the tumor to be CD2+, CD3+, CD5-, CD7+, TcR-gamma/delta+, CD4-, CD8+/-, CD56+, and CD11c+. The CD26 molecule was also expressed, and DPP IV activity was present, with the maximal activity detectable after 10 min of incubation. These results represent the initial description of enzymatically active CD26 in a T-cell malignancy, and raise the possibility that this molecule may be a participant in the pathogenetic mechanisms utilized by the neoplastic cells.

Adolescent↗
PubMed1998

Occupancy of dipeptidyl peptidase IV activates an associated tyrosine kinase and triggers an apoptotic signal in human hepatocarcinoma cells.

Dipeptidyl peptidase IV (CD26/DPP-IV) is an ectoenzyme expressed on different cell types. Signaling properties and functional consequences of the CD26 triggering have been elucidated mostly on T cells, where the molecule delivers a costimulatory signal that potentiates T-cell activation through the T-cell receptor. We conducted studies in the human hepatocarcinoma-derived PLC/PRF/5 cell line to examine the signal transduction through CD26 and its functional properties in the absence of other T-cell-specific membrane molecules. Engagement of CD26 in PLC/PRF/5 cells through a specific antibody induces tyrosine phosphorylation of several proteins with maximal intensity 15 minutes after the stimulation. This effect was under the negative regulatory control of CD45 tyrosine phosphatase, in that the addition of orthovanadate clearly enhanced the phosphorylation events. Using in vitro kinase assays with CD26 immunoprecipitates, we observed that a protein or proteins with kinase activity are coprecipitated with the CD26 molecule. In addition, unlike Jurkat T cells, in which CD26 expression exerts a protective effect against apoptosis, in PLC/PRF/5 cells CD26 occupancy delivers a potent apoptotic signal. This effect was also observed in HepG2 cells, thus indicating that it represents a more general phenomenon occurring in different liver neoplastic cell lines.

Apoptosis↗
PubMed2004

Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cells.

Lung cancer is the leading cause of cancer death. Lung cancers produce a variety of mitogenic growth factors that stimulate tumor cell proliferation and migration. The cell surface protease, dipeptidyl peptidase IV (DPPIV), is involved in diverse biologic functions, including peptide-mediated cellular growth and differentiation. DPPIV is expressed in various normal tissues, including lung tissue, and its expression is lost in many types of human cancers. DPPIV expression and its enzymatic activity are detected in normal bronchial and alveolar epithelium but different histologic subtypes of lung carcinomas lose DPPIV expression. To investigate the role of DPPIV in lung carcinoma, we examined the expression of DPPIV at both mRNA and protein levels in non small cell lung cancer (NSCLC) cell lines and normal human bronchial epithelial cells. DPPIV expression was detectable in normal lung epithelial cells, but was absent or markedly reduced in all NSCLC cell lines at both mRNA and protein levels. Restoration of DPPIV expression in NSCLC cells resulted in profound morphologic changes, inhibition of cell proliferation, anchorage-independent growth, in vitro cell migration and tumorigenicity in nude mice. DPPIV reexpression also correlated with increased p21 expression, leading to induction of apoptosis and cell cycle arrest in G1 stage. These effects were accompanied by increased expression of cell surface proteins, fibroblast-activating protein (Fapalpha) and CD44 that are associated with suppression of tumor growth and metastasis. Thus, DPPIV functions as a tumor suppressor, and its downregulation may contribute to the loss of growth control in NSCLC cells.

Animals↗
PubMed2004

Stromal cell-derived factor-1alpha-induced cell proliferation and its possible regulation by CD26/dipeptidyl peptidase IV in endometrial adenocarcinoma.

CD26/dipeptidylpeptidase IV (DPPIV) is a 110 kD membrane-bound extracellular peptidase with ubiquitous expressions, and has a variety of functional properties in the development of human malignancies as well as T-cell biology. According to recent reports, stromal cell derived factor-1alpha (SDF-1alpha), which is a good substrate for CD26/DPPIV, is expressed in various solid tumors and is involved in tumor development or metastasis. We investigated the expression of SDF-1alpha and its corresponding receptor, CXCR4, in human endometrial carcinoma (EMCA) tissues and the function of SDF-1alpha on EMCA cells with its regulation by CD26/DPPIV. We demonstrated that SDF-1alpha and CXCR4 were expressed in human EMCA, and these immunoreactivities were significantly low in Grade 3 EMCA, which was similar to that of CD26/DPPIV, compared to those in Grade 1 and Grade 2. Additionally, exogenous SDF-1alpha concentration was significantly lower in CD26/DPPIV-transfected EMCA cells than that in vector-transfected cells. Moreover, exogenous SDF-1alpha significantly stimulated cell proliferation in vector-transfected cells in a concentration dependent manner. In contrast, in CD26/DPPIV-transfected cells, there was no apparent effect on proliferation shown by the addition of exogenous SDF-1alpha. This is the first report showing a direct link between the SDF-1alpha/CXCR4 pathway with CD26/DPPIV in solid tumors, suggesting that CD26/DPPIV is likely to directly modulate various SDF-1alpha induced functions.

Adenocarcinoma↗
PubMed1995

CD26 (dipeptidyl peptidase IV/DPP IV) as a novel molecular marker for differentiated thyroid carcinoma.

In this report we show that CD26 (dipeptidyl peptidase IV/DPP IV) is a novel molecular marker for differentiated thyroid carcinoma. Northern-blot analysis of 22 various thyroid tissues revealed that CD26 is a more specific marker of differentiated thyroid carcinoma than 3 proto-oncogenes previously reported to increase mRNA expression in thyroid carcinomas: c-met, c-erbB-2 and EGF-R. A comparative study of 3 CD26 assays, Northern blotting, immunohistochemical staining and activity staining clearly showed that CD26 enzyme activity staining is the most specific assay for differentiated thyroid carcinoma, yet the easiest to perform. Activity staining of 216 thyroid tissues detected CD26 in all 52 papillary carcinomas and all 5 follicular carcinomas, while all 58 cases of Graves' disease were CD26-negative. Among benign neoplasms, 54 of 55 adenomatous goiters and 29 of 33 follicular adenomas were CD26 negative. Staining intensity of the enzyme activity was relative to the degree of CD26 mRNA expression. Southern-blot study showed no gene amplification or major translocation of the CD26 gene in 7 papillary carcinomas examined. Based on this study, ectopic expression of CD26 in differentiated thyroid carcinomas is thought to be mainly caused by increased CD26 mRNA expression. In conclusion, CD26 activity staining is a simple, specific assay which should be added to the usual pathological examinations in order to distinguish differentiated thyroid carcinomas from benign thyroid diseases.

Adolescent↗
PubMed2005

Development and resolution of experimental colitis in mice with targeted deletion of dipeptidyl peptidase IV.

Glucagon-like peptide-2 (GLP-2) is a potent intestinotrophic growth factor that enhances repair of damaged intestinal tissue. However, its bioactivity is limited by dipeptidyl peptidase IV (DPIV)-mediated degradation. We hypothesized that DPIV(-/-) mice would display an increased resistance to, and an enhanced recovery from, dextran sulfate sodium (DSS)-induced colitis compared to DPIV(+/+) mice. DPIV(+/+) and DPIV(-/-) mice consumed 2% DSS for 6 days, followed by a 15 day recovery period. Mice were killed at days 0, 3, 6, 9, 14, and 21 (n = 6-8) and the small intestine and colon removed for histological assessment of villus height, crypt depth, and crypt area. The epithelial cell proliferative labeling index was determined by proliferating cell nuclear antigen (PCNA) immunostaining. Small intestine, colon, and total body weight did not differ between DPIV(+/+) and DPIV(-/-) mice. Distal colon crypt depth did not differ significantly between DPIV(+/+) and DPIV(-/-) mice during the development of DSS-colitis or during the recovery phase. Similarly no significant effects were apparent on distal colon crypt area or PCNA labeling index between DPIV(+/+) and DPIV(-/-) during the development of and recovery from DSS-colitis. However, DPIV(-/-) mice still possessed significant levels of plasma DPIV-like activity. We conclude that loss of DPIV activity does not increase resistance to experimental colitis and hypothesize that other DPIV family members may also be involved in the cleavage of GLP-2.

Animals↗