title: Collagen degradation and neutrophilic infiltration: a vicious circle in inflammatory bowel disease.
abstract: OBJECTIVE
  Proline-glycine-proline (PGP) has been shown to have chemotactic effects on neutrophils via CXCR2 in several lung diseases. PGP is derived from collagen by the combined action of matrix metalloproteinase (MMP) 8 and/or MMP9 and prolyl endopeptidase (PE). We investigated the role of PGP in inflammatory bowel disease (IBD).
  
  
  METHODS
  In intestinal tissue from patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis, MMP8, MMP9 and PE were evaluated by ELISA, immunoblot and immunohistochemistry. Peripheral blood polymorphonuclear cell (PMN) supernatants were also analysed accordingly and incubated with collagen to assess PGP generation ex vivo. PGP levels were measured by mass spectrometry, and PGP neutralisation was achieved with a PGP antagonist and PGP antibodies.
  
  
  RESULTS
  In the intestine of patients with IBD, MMP8 and MMP9 levels were elevated, while PE was expressed at similar levels to control tissue. PGP levels were increased in intestinal tissue of patients with IBD. Similar results were obtained in intestine from DSS-treated mice. PMN supernatants from patients with IBD were far more capable of generating PGP from collagen ex vivo than healthy controls. Furthermore, PGP neutralisation during DSS-induced colitis led to a significant reduction in neutrophil infiltration in the intestine.
  
  
  CONCLUSIONS
  The proteolytic cascade that generates PGP from collagen, as well as the tripeptide itself, is present in the intestine of patients with IBD and mice with DSS-induced colitis. PGP neutralisation in DSS-treated mice showed the importance of PGP-guided neutrophilic infiltration in the intestine and indicates a vicious circle in neutrophilic inflammation in IBD.
authors.affiliation: Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, , Utrecht, The Netherlands.
authors.forename: Pim J
authors.initials: PJ
authors.lastname: Koelink
authors.forename: Saskia A
authors.initials: SA
authors.lastname: Overbeek
authors.forename: Saskia
authors.initials: S
authors.lastname: Braber
authors.forename: Mary E
authors.initials: ME
authors.lastname: Morgan
authors.forename: Paul A J
authors.initials: PA
authors.lastname: Henricks
authors.forename: Mojtaba
authors.initials: M
authors.lastname: Abdul Roda
authors.forename: Hein W
authors.initials: HW
authors.lastname: Verspaget
authors.forename: Simone C
authors.initials: SC
authors.lastname: Wolfkamp
authors.forename: Anje A
authors.initials: AA
authors.lastname: te Velde
authors.forename: Caleb W
authors.initials: CW
authors.lastname: Jones
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Jackson
authors.forename: J Edwin
authors.initials: JE
authors.lastname: Blalock
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
authors.forename: John A W
authors.initials: JA
authors.lastname: Kruijtzer
authors.forename: Johan
authors.initials: J
authors.lastname: Garssen
authors.forename: Gert
authors.initials: G
authors.lastname: Folkerts
authors.forename: Aletta D
authors.initials: AD
authors.lastname: Kraneveld
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism* / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020556:Neutrophil Infiltration / Q000502:physiology*; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000378:metabolism; D055815:Young Adult
chemical_list: D003094:Collagen; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9