Fig 2: In inflammatory bowel disease (IBD), intestinal damage by proteases indicates a vicious circle of events leading to proline–glycine–proline (PGP)-induced neutrophilic transmigration. In IBD, triggering of the epithelial layer by bacteria or their products leads to extensive release of CXCL8 by epithelial cells and subsequent CXCL8–CXCR1/2-mediated transmigration of neutrophils from the circulation (left panel). Invading neutrophils produce large amounts of matrix metalloproteinase (MMP) 8 and MMP9, which proteolytically cleave collagen into small fragments. These collagen fragments are further cleaved to the tripeptide, PGP, by epithelial- and neutrophil-derived prolyl endopeptidase (PE) (middle panel). PGP is N-terminally acetylated by an as yet unknown enzyme that is at least produced by neutrophils. (N-Ac-)PGP causes neutrophil chemotaxis and stimulates recruited neutrophils to produce CXCL8 (right panel), leading to a self-maintaining chronic situation.

Fig 3: Proteases in dextran sodium sulfate (DSS)-induced colitis. Intestinal prolyl endopeptidase (PE) activity (A) of huCXCR2 knock-in mice treated with 2-day cycles of DSS over time confirmed by immunoblot with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a loading control (B). Active and total matrix metalloproteinase 9 (MMP9) levels (C) were confirmed by zymography (D), and MMP8 levels (E) were confirmed by immunoblot with GAPDH as a loading control (F). All values are mean+SEM (n=3–8). *p<0.05 versus day 0 (control); **p<0.01 versus day 0. Statistical analysis was by one-way analysis of variance followed by Dunnett's multiple comparison test. AMC, 7-amido-4-methylcoumarin.