title: N-acetylated Proline-Glycine-Proline induced G-protein dependent chemotaxis of neutrophils is independent of CXCL8 release.
abstract: Chronic inflammation in lung diseases contributes to lung tissue destruction leading to the formation of chemotactic collagen fragments such as N-acetylated Proline-Glycine-Proline (N-ac-PGP). In this study, we investigated in more detail the mechanism of action of N-ac-PGP in neutrophilic inflammation. N-ac-PGP was chemotactic for human neutrophils via pertussis toxin sensitive G protein-coupled receptors in vitro and directly activated this cell type, which led to cytosolic calcium mobilization and release of CXCL8. Furthermore, using a selective CXCR2 antagonist confirmed that N-ac-PGP-induced neutrophil chemotaxis is mediated through CXCR2 activation. To determine whether N-ac-PGP was solely responsible for the migration and activation of human neutrophils in vitro and not the released CXCL8 upon stimulation with N-ac-PGP, an antibody directed against CXCL8 was used. Performing chemotaxis and calcium influx assays in the presence of this antibody did not alter the effects of N-ac-PGP whereas effects of CXCL8 were attenuated. These experiments indicate that N-ac-PGP, in addition to the direct induction of chemotaxis, also directly activates neutrophils to release CXCL8. In vivo, this may lead in the long term to a self-maintaining situation enhanced by both N-ac-PGP and CXCL8, leading to a further increase in neutrophil infiltration and chronic inflammation.
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands. S.A.Overbeek@uu.nl
authors: Saskia A
authors: SA
authors: Overbeek
authors: Paul A J
authors: PA
authors: Henricks
authors: Anja I
authors: AI
authors: Srienc
authors: Pim J
authors: PJ
authors: Koelink
authors: Petra
authors: P
authors: de Kruijf
authors: Herman D
authors: HD
authors: Lim
authors: Martine J
authors: MJ
authors: Smit
authors: Guido J R
authors: GJ
authors: Zaman
authors: Johan
authors: J
authors: Garssen
authors: Frans P
authors: FP
authors: Nijkamp
authors: Aletta D
authors: AD
authors: Kraneveld
authors: Gert
authors: G
authors: Folkerts
mesh_terms: D000906:Antibodies / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D037342:Pertussis Toxin / Q000633:toxicity; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism
chemical_list: D000906:Antibodies; D007093:Imidazoles; D016209:Interleukin-8; C428643:N-acetyl-proline-glycine-proline; D009842:Oligopeptides; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D023063:Receptors, Interleukin-8B; D003094:Collagen; D037342:Pertussis Toxin; D020962:Heterotrimeric GTP-Binding Proteins; D002118:Calcium