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

Apr 13, 2004Journal of leukocyte biology

Combined effects of inflammatory signals on neutrophil activation and movement

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Abstract

Chemokines may enhance neutrophil migration in a dose-dependent manner, with synergy observed between various chemokines.

The chemokine concentration and the duration of the gradient influence leukocyte infiltration in inflamed tissues.
At suboptimal concentrations, neutrophils may need additional stimuli for full activation.
Synergistic effects were observed between regakine-1 and interleukin-8, enhancing neutrophil chemotaxis.
Other chemokines, such as MCP-1, MCP-2, and MCP-3, also increased neutrophil chemotaxis towards IL-8 in a dose-dependent manner.
The combination of IL-8 and MCP-3 led to greater neutrophil shape change.
A specific CXCR4 inhibitor significantly reduced the synergy between SDF-1alpha and IL-8.

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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.

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

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