Dipeptidyl peptidase-4 expression is reduced in Crohn's disease

作者：Moran G W; O'Neill C; Padfield P; McLaughlin J T^*

来源：Regulatory Peptides, 2012, 177(1-3): 40-45.

DOI：10.1016/j.regpep.2012.04.006

• Dipeptidyl peptidase 4
• Enteroendocrine
• Intestinal inflammation
• Crohn's disease

Background: Dipeptidyl peptidase 4 (DP4) is a serine protease that preferentially cleaves N-terminal dipeptides from polypeptides containing proline or alanine as the penultimate amino acid. DP4 inactivates glucagon like peptide-2 (GLP-2), a trophic peptide with cytoprotective and reparative properties in the injured gut; therefore DP4 potentially inhibits repair processes. DP4 also modulates the activity of GLP-1 and polypeptide YY (PYY) which regulate appetite and motility. No data are yet available on the tissue and plasma expression of DP4 in inflammatory bowel disease (IBD).
Methods: Tissue and plasma were studied from active CD and healthy controls for DP4 quantification. Experiments were also carried out in a reductionist Caco-2 Cell line model of intestinal inflammation with TNF alpha incubation. DP4 expression was studied by tissue Western blotting and plasma enzymelinked immunosorbent assay (ELISA), in addition to quantitative polymerase chain reaction (qPCR).
Results: There was a similar to 2.7-fold decrease in DP4 protein in CD tissue (p = 0.05). Plasma DP4 in CD was also significantly lower than the control group. A negative correlation between plasma DP4 levels and inflammatory activity as measured by C-reactive protein was observed. In Caco-2 cells an similar to 18-fold increase (p<0.0001) in DP4 protein expression was seen after incubation with TNF alpha at a concentration of 25 ng/mu l for 48 hours paralleled by a 2-fold increase in DP4 mRNA.
Discussion: DP4 is reduced in tissue and plasma in active Crohn's disease. This is unlikely to represent simple downregulation induced by inflammation since the key proinflammatory cytokine strongly upregulated DP4 expression in Caco-2 cells. Clearly a more complex situation exists in vivo. We propose that reduced DP4 activity limits the cleavage of regulatory peptides, for example potentiating the trophic signal from GLP-2. Pharmacological DP4 inhibition may present an additional therapeutic target in IBD.

• 出版日期2012-8-20