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Antimicrobial Agents and Chemotherapy, May 2005, p. 1727-1732, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1727-1732.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Immunomodulatory Activities of Small Host Defense Peptides

Dawn M. E. Bowdish,1 Donald J. Davidson,2 Monisha G. Scott,1,3 and Robert E. W. Hancock1*

Centre for Microbial Diseases and Immunity Research, University of British Columbia, 2259 Lower Mall Road, Vancouver, British Columbia, Canada V6T 1Z4,1 MRC Centre for Inflammation, Edinburgh University Medical School, Teviot Place, Edinburgh EH8 9AG, Scotland, United Kingdom,2 Inimex Pharmaceuticals, 2259 Lower Mall Road, Vancouver, British Columbia, Canada V6T 1Z43

Received 23 November 2004/ Returned for modification 29 November 2004/ Accepted 18 January 2005

Recent studies have demonstrated that in addition to their antimicrobial activity, cationic host defense peptides, like the human cathelicidin LL-37, perform many activities relating to innate immunity, including the induction or modulation of chemokine and cytokine production, alteration of gene expression in host cells, and inhibition of proinflammatory responses of host cells to bacterial components such as lipopolysaccharide (LPS) in vitro and in vivo. To investigate if these properties are shared by smaller peptides, two cathelicidin peptides derived from bovine neutrophils, the 13-mer indolicidin and Bac2A, a linear 12-amino-acid derivative of bactenecin, were compared to the 37-amino-acid peptide LL-37. Indolicidin, like LL-37, inhibited LPS-induced tumor necrosis factor alpha (TNF-{alpha}) secretion, even when added up to an hour after the addition of Escherichia coli O111:B4 LPS to the human macrophage/monocyte-like THP-1 cell line. In contrast, Bac2A demonstrated no significant antiendotoxin activity. At low concentrations, indolicidin and LL-37 acted synergistically to suppress LPS-induced production of TNF-{alpha}. Indolicidin was analogous to LL-37 in its ability to induce the production of the chemokine interleukin-8 (IL-8) in a human bronchial cell line, 16HBE14o–, but it was unable to induce production of IL-8 in THP-1 cells. In contrast, Bac2A was unable to induce IL-8 in either cell type. Conversely, Bac2A was chemotactic for THP-1 cells at concentrations between 10 and 100 µg/ml, while indolicidin and LL-37 were not chemotactic at these concentrations for THP-1 cells. This indicates that in addition to the potential for direct microbicidal activity, cationic host defense peptides may have diverse and complementary abilities to modulate the innate immune response.

* Corresponding author. Mailing address: Centre for Microbial Diseases and Immunity Research, University of British Columbia, 2259 Lower Mall Road, Vancouver, British Columbia, Canada V6T 1Z4. Phone: (604) 822-2682. Fax: (604) 827-5566. E-mail: bob{at}cmdr.ubc.ca.

Antimicrobial Agents and Chemotherapy, May 2005, p. 1727-1732, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1727-1732.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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