The human lactoferrin-derived peptide hLF1-11 exerts immunomodulatory effects by specific inhibition of myeloperoxidase activity

Because of their ability to eliminate pathogens and to modulate various host immune responses, antimicrobial peptides are considered as candidate agents to fight infections by (antibiotic-resistant) pathogens. We recently reported that hLF1-11 (GRRRRSVQWCA), an antimicrobial peptide derived from the...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2012-05, Vol.188 (10), p.5012-5019
Main Authors: van der Does, Anne M, Hensbergen, Paul J, Bogaards, Sylvia J, Cansoy, Medine, Deelder, André M, van Leeuwen, Hans C, Drijfhout, Jan W, van Dissel, Jaap T, Nibbering, Peter H
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents
Cells, Cultured
Humans
Immunologic Factors - physiology
Lactoferrin - physiology
Monocytes - enzymology
Monocytes - immunology
Peroxidase - antagonists & inhibitors
Peroxidase - metabolism
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Summary:Because of their ability to eliminate pathogens and to modulate various host immune responses, antimicrobial peptides are considered as candidate agents to fight infections by (antibiotic-resistant) pathogens. We recently reported that hLF1-11 (GRRRRSVQWCA), an antimicrobial peptide derived from the N terminus of human lactoferrin, displays diverse modulatory activities on monocytes, thereby enhancing their actions in innate immune responses. The aim of this study was to identify the cellular target of hLF1-11 that mediates these effects. Results revealed that hLF1-11 binds and subsequently penetrates human monocytes, after which it inhibits the enzymatic activities of myeloperoxidase (MPO). Moreover, a chemical inhibitor of MPO (aminobenzoic acid hydrazide) mimicked the effects of hLF1-11 on the inflammatory response by monocytes and on monocyte-macrophage differentiation. Computer-assisted molecular modeling predicted that hLF1-11 can bind to the edge of and within the crevice of the active site of MPO. Experiments with a set of hLF1-11 peptides with amino acid substitutions identified the stretch of arginines and the cysteine at position 10 as pivotal in these immunomodulatory properties of hLF1-11. We conclude that hLF1-11 may exert its modulatory effects on human monocytes by specific inhibition of MPO activity.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1102777