Abstract
The innate immune response against micro‐organisms is mediated by phagocytes, attracted by chemokines and other G protein‐coupled receptor (GPCR) ligands. Originally, we observed increased neutrophil migration by the interaction of inflammatory CXC chemokines such as IL‐8/CXCL8 and granulocyte chemotactic protein (GCP)‐2/CXCL6 with regakine‐1, a CC chemokine constitutively present in plasma. We here demonstrate statistically significant synergy between regakine‐1 and the neutrophil attractants C5a or IL‐8/CXCL8 in inducing neutrophil shape change and migration under agarose. In addition, regakine‐1 attracted human bone marrow granulocytes and enhanced their chemotactic response to IL‐8/CXCL8 in a dose‐dependent manner. Thus, plasma chemokines may regulate the number of circulating leukocytes under homeostatic conditions and may facilitate extra recruitment of bone marrow neutrophils during inflammation. Indeed, in vivo, regakine‐1 provoked a mild neutrophilia in rabbits upon intravenous injection. We also observed that the CC chemokines regakine‐1 and monocyte chemotactic protein‐3/CCL7 as well as the CXC chemokine stromal cell‐derived factor‐1α/CXCL12 co‐operated with murine GCP‐2 after intraperitoneal co‐administration to increase neutrophil influx in mice. These data demonstrate that inducible and constitutive GPCR ligands synergize to enhance inflammation and facilitate a more effective immune response.