Interplay between signaling via the formyl peptide receptor (FPR) and chemokine receptor 3 (CCR3) in human eosinophils.
Eosinophils express the chemoattractant receptors CCR3 and FPR. CCR3 binds several agonists such as eotaxin-1, -2, and -3 and RANTES, whereas the FPR binds the formylated tripeptide fMLP and a host of other ligands. The aim of this study was to investigate if there is interplay between these two receptors regarding the elicitation of migration and respiratory burst in human blood-derived eosinophils. Inhibition of the FPR with the antagonists CyH and boc-MLP abrogated the migration of eosinophils toward all of the CCR3 agonists. Similar results were seen when the FPR was desensitized with its cognate ligand, fMLP. In contrast, the respiratory burst triggered by eotaxin-1 was not inhibited by CyH. Thus, signals evoked via the FPR caused unidirectional down-regulation of CCR3-mediated chemotaxis but not respiratory burst in human eosinophils. The underlying mechanism was neither reduced ability of the CCR3 ligand eotaxin-1 to bind to CCR3 nor down-regulation of CCR3 from the cell surface. Finally, confocal microscopy and adFRET analysis ruled out homo- or heterodimer formation between FPR and/or CCR3 as an explanation for the reduction in chemotaxis via CCR3. Pharmacologic inhibition of signal transduction molecules showed that the release of free oxygen radicals in response to eotaxin-1 compared with fMLP is relatively more dependent on the p38 MAPK pathway.
Department of Clinical Bacteriology, Göteborg University, Göteborg, Sweden. Lena.Svensson@cancer.org.uk
Lena
L
Svensson
Elin
E
Redvall
Marianne
M
Johnsson
Anna-Lena
AL
Stenfeldt
Claes
C
Dahlgren
Christine
C
Wennerås
D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054413:Chemokine CCL11 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D053138:Cyclohexenes / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D008024:Ligands; D018613:Microscopy, Confocal; D009842:Oligopeptides / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000276:immunology*; D054397:Receptors, CCR3 / Q000819:agonists / Q000378:metabolism*; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D053138:Cyclohexenes; D005609:Free Radicals; D008024:Ligands; D009842:Oligopeptides; D054397:Receptors, CCR3; D044042:Receptors, Formyl Peptide; C052568:cyclohexene; C088189:N-tert-butyloxycarbonylnorleucyl-leucyl-phenylalanine; D048051:p38 Mitogen-Activated Protein Kinases