Synergy between proinflammatory ligands of G protein-coupled receptors in neutrophil activation and migration

Journal of Leukocyte Biology

Mieke Gouwy¹  Julie Catusse¹  Sofie Struyf¹  Jo Van Damme¹  Paul Proost¹ 

[1] Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, BelgiumLaboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, BelgiumLaboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Belgium

关键词: chemokines;    chemotaxis;    shape change;    C5a;    receptor;   

DOI  :  10.1189/jlb.1003479

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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-1α (SDF-1α/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-1α and IL-8 significantly. SDF-1α, 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-1α) to enhance the inflammatory response.

【 授权许可】

Unknown