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Published online before print May 18, 2009
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1008638

Received for publication October 17, 2008.
Revised March 5, 2009.
Accepted for publication April 10, 2009.

Article

CC chemokine ligand-2 synergizes with the nonchemokine G protein-coupled receptor ligand fMLP in monocyte chemotaxis, and it cooperates with the TLR ligand LPS via induction of CXCL8

Mieke Gouwy *, Sofie Struyf *, Hannelien Verbeke *, Willy Put *, Paul Proost *, Ghislain Opdenakker {dagger}, and Jo Van Damme *@

*Laboratory of Molecular Immunology and{dagger}Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium

@ To whom correspondence should be addressed. E-mail: jo.vandamme{at}rega.kuleuven.be.


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Abstract

During inflammatory reactions, endogenously produced cytokines and chemokines act in a network and interact with hormones and neurotransmitters to regulate host immune responses. These signaling circuitries are even more interfaced during infections, when microbial agonists activate TLR, RLR, and NLR receptors. On the basis of the discovery of synergy between chemokines for neutrophil attraction, we extend here this phenomenon between the chemokine MCP-1/CCL2 and the GPCR ligand N-formyl-methionyl-leucyl-phenylalanine or the TLR4 agonist LPS on monocytes. In fact, the bacterial tripeptide fMLP, but not the cytokines IL-1{beta} or IFN-{gamma}, significantly and dose-dependently synergized with CCL2 in monocyte chemotaxis. Furthermore, LPS rapidly induced the expression of interleukin-8/CXCL8 but not of the CCL2 receptor CCR2 in monocytic cells. In turn, the induced CXCL8 synergized with CCL2 for mononuclear cell chemotaxis, and the chemotactic effect was mediated by CXCR1/CXCR2, because CXCL8 receptor antagonists or antibodies were capable of blocking the synergy, while keeping the responsiveness to CCL2 intact. These data recapitulate in vitro the complexity of innate immune regulation, provide a novel mechanism of enhancing monocyte chemotaxis during bacterial infections with gram-negative bacteria and demonstrate the importance of local contexts in inflammatory and infectious insults.

Key Words: chemokines • migration • cytokines