title: The human lactoferrin-derived peptide hLF1-11 exerts immunomodulatory effects by specific inhibition of myeloperoxidase activity.
abstract: 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.
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
authors.forename: Anne M
authors.initials: AM
authors.lastname: van der Does
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hensbergen
authors.forename: Sylvia J
authors.initials: SJ
authors.lastname: Bogaards
authors.forename: Medine
authors.initials: M
authors.lastname: Cansoy
authors.forename: André M
authors.initials: AM
authors.lastname: Deelder
authors.forename: Hans C
authors.initials: HC
authors.lastname: van Leeuwen
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Jaap T
authors.initials: JT
authors.lastname: van Dissel
authors.forename: Peter H
authors.initials: PH
authors.lastname: Nibbering
mesh_terms: D000900:Anti-Bacterial Agents; D002478:Cells, Cultured; D006801:Humans; D007155:Immunologic Factors / Q000502:physiology*; D007781:Lactoferrin / Q000502:physiology*; D009000:Monocytes / Q000201:enzymology / Q000276:immunology; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D007155:Immunologic Factors; D009195:Peroxidase; D007781:Lactoferrin