AAC Accepts, published online ahead of print on 28 April 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00028-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The human CXC-chemokine Granulocyte Chemotactic Protein 2 (GCP–2)/CXCL6 possesses membrane disrupting properties and is antibacterial

Helena M. Linge^*, Mattias Collin, Pontus Nordenfelt, Matthias Mörgelin, Martin Malmsten, and Arne Egesten

Divisions of Infection, and Respiratory Medicine, Department of Clinical Sciences Lund, Lund University, SE–221 84 Lund, and Department of Pharmacy, Uppsala University, SE-751 23 Uppsala, Sweden

^* To whom correspondence should be addressed. Email: hlinge{at}nshs.edu.

Granulocyte chemotactic protein (GCP)–2/CXCL6 is a CXC-chemokine expressed by macrophages, epithelial, and mesenchymal cells during inflammation. Through binding and activation of its receptors (CXCR1 and CXCR2), it exerts neutrophil-activating and angiogenetic activities. Here we show that GCP–2/CXCL6 itself is antibacterial. Antibacterial activity against Gram-positive and Gram-negative pathogenic bacteria of relevance to mucosal infections was seen at below micromolar concentrations (MBC₅₀=0.063 ±0.01- 0.37 ±0.03). In killed bacteria, GCP–2/CXCL6 associated with bacterial surfaces which showed membrane disruption and leakage. A structural prediction indicated the presence of three anti-parallel NH₂-terminal -sheets and a short amphipathic COOH-terminal -helix, the latter a feature typical of antimicrobial peptides. However, when comparing the synthetic derivatives corresponding to the NH₂-terminal (50 amino acids) and COOH-terminal (19 amino acids, corresponding to the putative -helix) respectively, a higher antibacterial activity was observed in the NH₂-derived peptide, indicating that the holopeptide is necessary for full antibacterial activity. An artificial model of bacterial membranes confirmed these findings. The helical content of GCP-2/CXCL6 in the presence or absence of lipopolysaccharide or negatively charged membranes was studied by circular dichroism. Like many antibacterial peptides, membrane disruption by GCP–2/CXCL6 was dose-dependently reduced in the presence of NaCl which we here demonstrate, inhibited the binding of the peptide to the bacterial surface. Compared with CXC chemokines ENA–78/CXCL5 and NAP–2/CXCL7, GCP–2/CXCL6 showed a 90-fold higher antibacterial activity. Taken together, GCP/CXCL6, in addition to its chemotactic and angiogenic properties, is likely to contribute to direct antibacterial activity during localized infection.

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