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Antimicrobial Agents and Chemotherapy, July 2008, p. 2599-2607, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.00028-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Human CXC Chemokine Granulocyte Chemotactic Protein 2 (GCP-2)/CXCL6 Possesses Membrane-Disrupting Properties and Is Antibacterial{triangledown}

Helena M. Linge,1* Mattias Collin,1 Pontus Nordenfelt,1 Matthias Mörgelin,1 Martin Malmsten,2 and Arne Egesten3

Divisions of Infection,1 Respiratory Medicine, Department of Clinical Sciences Lund, Lund University, SE-221 84 Lund,3 Department of Pharmacy, Uppsala University, SE-751 23 Uppsala, Sweden2

Received 8 January 2008/ Returned for modification 4 February 2008/ Accepted 16 April 2008

Granulocyte chemotactic protein 2 (GCP-2)/CXCL6 is a CXC chemokine expressed by macrophages and epithelial and mesenchymal cells during inflammation. Through binding and activation of its receptors (CXCR1 and CXCR2), it exerts neutrophil-activating and angiogenic 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 submicromolar concentrations (minimal bactericidal concentration at which 50% of strains tested were killed, 0.063 ± 0.01 to 0.37 ± 0.03 µM). In killed bacteria, GCP-2/CXCL6 associated with bacterial surfaces, which showed membrane disruption and leakage. A structural prediction indicated the presence of three antiparallel NH2-terminal β-sheets and a short amphipathic COOH-terminal {alpha}-helix; the latter feature is typical of antimicrobial peptides. However, when the synthetic derivatives corresponding to the NH2-terminal (50 amino acids) and COOH-terminal (19 amino acids, corresponding to the putative {alpha}-helix) regions were compared, higher antibacterial activity was observed for the NH2-terminus-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. As with 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.

* Corresponding author. Present address: Section for Cardiopulmonary Research, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030. Phone: (516) 562-3464. Fax: (516) 562-1022. E-mail: hlinge{at}nshs.edu

{triangledown} Published ahead of print on 28 April 2008.

Antimicrobial Agents and Chemotherapy, July 2008, p. 2599-2607, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.00028-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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