Abstract | BACKGROUND: MATERIALS AND METHODS: Wildtype (WT) and DPIV(-/-) mice consumed 2% DSS in drinking water for 6 days to induce colitis. Mice were treated with saline or the DP inhibitors Ile-Pyrr-(2-CN)*TFA or Ile-Thia. DP mRNA and enzyme levels were measured in the colon. Glucagon-like peptide (GLP)-2 and GLP-1 concentrations were determined by radioimmunoassay, regulatory T-cells (Tregs) by fluorescence activated cell sorting (FACS) on FOXp3+T cells in blood, and neutrophil infiltration assessed by myeloperoxidase (MPO) assay. RESULTS: DP8 and DP2 mRNA levels were increased (P < 0.05) in WT+saline mice compared to untreated WT mice with colitis. Cytoplasmic DP enzyme activity was increased (P < 0.05) in DPIV(-/-) mice at day 6 of DSS, while DP2 activity was increased (P < 0.05) in WT mice with colitis. GLP-1 (63%) and GLP-2 (50%) concentrations increased in WT+Ile-Pyrr-(2-CN)*TFA mice compared to day-0 controls. MPO activity was lower in WT+Ile-Thia and WT+Ile-Pyrr-(2-CN)*TFA treated mice compared to WT+saline (P < 0.001) at day 6 colitis. CONCLUSIONS: DP expression and activity are differentially regulated during DSS colitis, suggesting a pathophysiological role for these enzymes in human inflammatory bowel disease (IBD). DP inhibitors impaired neutrophil recruitment and maintenance of the Treg population during DSS- colitis, providing further preclinical evidence for the potential therapeutic use of these inhibitors in IBD. Finally, DPIV appears to play a critical role in mediating the protective effect of DP inhibitors.
|
Authors | Roger Yazbeck, Melanie L Sulda, Gordon S Howarth, Andre Bleich, Kerstin Raber, Stephan von Hörsten, Jens Juul Holst, Catherine A Abbott |
Journal | Inflammatory bowel diseases
(Inflamm Bowel Dis)
Vol. 16
Issue 8
Pg. 1340-51
(Aug 2010)
ISSN: 1536-4844 [Electronic] England |
PMID | 20186930
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Dipeptidyl-Peptidase IV Inhibitors
- Glucagon-Like Peptide 2
- Glucagon-Like Peptide 1
- Dextran Sulfate
- Peroxidase
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
|
Topics |
- Animals
- Colitis
(chemically induced, enzymology)
- Colon
(chemistry, enzymology)
- Dextran Sulfate
(pharmacology)
- Dipeptidyl-Peptidase IV Inhibitors
(pharmacology)
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
(antagonists & inhibitors, biosynthesis, genetics)
- Disease Models, Animal
- Glucagon-Like Peptide 1
(analysis)
- Glucagon-Like Peptide 2
(analysis)
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neutrophil Infiltration
- Peroxidase
(analysis)
- T-Lymphocytes, Regulatory
(drug effects)
|