The collagen-breakdown product N-acetyl-Proline-Glycine-Proline (N-α-PGP) does not interact directly with human CXCR1 and CXCR2

Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
European journal of pharmacology (Impact Factor: 2.53). 09/2010; 643(1):29-33. DOI: 10.1016/j.ejphar.2010.06.017
Source: PubMed


Neutrophils transmigrate from the blood into inflamed tissue via the interaction of chemokines produced in this tissue with chemokine receptors, such as CXCR1 and CXCR2, that are expressed on the membranes of neutrophils. Subsequently, activation of neutrophils will in turn lead to increased tissue damage and thereby enhanced clinical symptoms of inflammatory diseases like chronic obstructive pulmonary disease, inflammatory bowel disease and psoriasis. Besides chemokines, also the collagen-breakdown product N-acetyl-Proline-Glycine-Proline (N-alpha-PGP) attracts neutrophils. In a recent article (Weathington et al., 2006) it was suggested that N-alpha-PGP exerts its effect via CXCR1 and CXCR2. In this study, we show that N-alpha-PGP, in contrast to CXCL8, does not directly activate or interact with CXCR1 or CXCR2. N-alpha-PGP was not able to displace the radioligand [(125)I]CXCL8 from CXCR1 and CXCR2 expressing HEK293T cells or neutrophils. In addition, N-alpha-PGP did not displace the radioligand [(3)H]-SB265610, a CXCR2 antagonist, from CXCR2 expressing cells. Furthermore, N-alpha-PGP was not able to activate G protein signalling in cells expressing CXCR1 and CXCR2. N-alpha-PGP was also not able to recruit beta-arrestin2, an intracellular scaffolding protein involved in G protein-independent signalling, in cells expressing CXCR2. These studies indicate that N-alpha-PGP is not a ligand of CXCR1 or CXCR2.

40 Reads
  • Source
    • "In all likelihood, this effect was observed due to not preincubating a low affinity CXCR ligand (Ac-PGP) with PMNs prior to incubation with the higher affinity ligand (IL-8) in the radioreceptor assay. In addition, these authors claim that Ac-PGP does not activate G-proteins but it is difficult for us to see how this would be possible since Ac-PGP is clearly chemotactic for PMNs as demonstrated in this group's manuscript as well as others [16], [19], [42], [43] and PMN chemotaxis is mediated through G-protein coupled receptors and activation of G-proteins. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic neutrophilic inflammation is a poorly understood feature in a variety of diseases with notable worldwide morbidity and mortality. We have recently characterized N-acetyl Pro-Gly-Pro (Ac-PGP) as an important neutrophil (PMN) chemoattractant in chronic inflammation generated from the breakdown of collagen by the actions of MMP-9. MMP-9 is present in the granules of PMNs and is differentially released during inflammation but whether Ac-PGP contributes to this ongoing proteolytic activity in chronic neutrophilic inflammation is currently unknown. Utilizing isolated primary blood PMNs from human donors, we found that Ac-PGP induces significant release of MMP-9 and concurrently activates the ERK1/2 MAPK pathway. This MMP-9 release is attenuated by an inhibitor of ERK1/2 MAPK and upstream blockade of CXCR1 and CXCR2 receptors with repertaxin leads to decreased MMP-9 release and ERK 1/2 MAPK activation. Supernatants obtained from PMNs stimulated by Ac-PGP generate more Ac-PGP when incubated with intact collagen ex vivo; this effect is inhibited by an ERK1/2 pathway inhibitor. Finally, clinical samples from individuals with CF demonstrate a notable correlation between Ac-PGP (as measured by liquid chromatography-tandem mass spectrometry) and MMP-9 levels even when accounting for total PMN burden. These data indicate that ECM-derived Ac-PGP could result in a feed-forward cycle by releasing MMP-9 from activated PMNs through the ligation of CXCR1 and CXCR2 and subsequent activation of the ERK1/2 MAPK, highlighting for the first time a matrix-derived chemokine (matrikine) augmenting its generation through a discrete receptor/intracellular signaling pathway. These findings have notable implications to the development unrelenting chronic PMN inflammation in human disease.
    PLoS ONE 05/2011; 6(1):e15781. DOI:10.1371/journal.pone.0015781 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The altered activity of a neutrophil enzyme promotes the type of persistent lung inflammation seen in chronic pulmonary disease and cystic fibrosis.
    Science 10/2010; 330(6000):40-1. DOI:10.1126/science.1196017 · 33.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In France, the majority of the electricity generated is derived from nuclear energy which has a low CO2 footprint.A preliminary analysis showed us that, in the French specific context, without any new nuclear power plant construction, the emission of several millions tons of CO2 could be avoided by using a CO2 to fuel technology to adjust the electricity produced by nuclear energy to the electricity grid demand. This will not only mitigate CO2 emissions but could also increase nuclear economic competitiveness.Possibilities of direct using nuclear heat are also under investigation, to improve the efficiency of the global system of conversion.
    Energy Procedia 12/2011; 4:2113-2120. DOI:10.1016/j.egypro.2011.02.095
Show more