title: Synergy between proinflammatory ligands of G protein-coupled receptors in neutrophil activation and migration.
abstract: The chemokine dose and the time period during which the chemotactic gradient is established determine the number of leukocytes that infiltrate inflamed tissues. At suboptimal chemokine concentrations, neutrophils may require a priming agent or a second stimulus for full activation. An interesting mode of cooperative action to reach maximal migration is synergy between chemokines. This was first observed between the plasma CC chemokine regakine-1 and the tissue CXC chemokine ligand interleukin-8 (IL-8/CXCL8) in neutrophil chemotaxis. Addition of antibodies against IL-8 or regakine-1 in the Boyden microchamber assay abrogated this synergy. Other CC chemokines, such as CC chemokine ligand-2 monocyte chemotactic protein-1 (MCP-1/CCL2), MCP-2 (CCL8), and MCP-3 (CCL7) as well as the CXC chemokine receptor-4 (CXCR4) agonist stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12), also dose-dependently enhanced neutrophil chemotaxis toward a suboptimal concentration of IL-8. These chemokines synergized equally well with the anaphylatoxin C5a in neutrophil chemotaxis. Alternatively, IL-8 and C5a did not synergize with an inactive precursor form of CXCL7, connective tissue-activating peptide-III/CXCL7, or the chemoattractant neutrophil-activating peptide-2/CXCL7. In the chemotaxis assay under agarose, MCP-3 dose-dependently increased the migration distance of neutrophils toward IL-8. In addition, the combination of IL-8 and MCP-3 resulted in enhanced neutrophil shape change. AMD3100, a specific CXCR4 inhibitor, reduced the synergistic effect between SDF-1alpha and IL-8 significantly. SDF-1alpha, but not MCP-1, synergized with IL-8 in chemotaxis with CXCR1-transfected, CXCR4-positive Jurkat cells. Thus, proinflammatory chemokines (IL-8, MCP-1), coinduced during infection in the tissue, synergize with each other or with constitutive chemokines (regakine-1, SDF-1alpha) to enhance the inflammatory response.
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Gouwy
authors.forename: Sofie
authors.initials: S
authors.lastname: Struyf
authors.forename: Julie
authors.initials: J
authors.lastname: Catusse
authors.forename: Paul
authors.initials: P
authors.lastname: Proost
authors.forename: Jo
authors.initials: J
authors.lastname: Van Damme
mesh_terms: D002118:Calcium / Q000378:metabolism; D018925:Chemokines / Q000494:pharmacology*; D019742:Chemokines, CC / Q000494:pharmacology; D019743:Chemokines, CXC / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D015936:Complement C5a / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D019169:Jurkat Cells; D008024:Ligands; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D019718:Receptors, CXCR4 / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000276:immunology; D014162:Transfection
chemical_list: D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D016209:Interleukin-8; D008024:Ligands; D019718:Receptors, CXCR4; D043562:Receptors, G-Protein-Coupled; D023062:Receptors, Interleukin-8A; D015936:Complement C5a; D002118:Calcium