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.

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    • "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. "
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