title: Antimicrobial peptide hLF1-11 directs granulocyte-macrophage colony-stimulating factor-driven monocyte differentiation toward macrophages with enhanced recognition and clearance of pathogens.
abstract: The human lactoferrin-derived peptide hLF1-11 displays antimicrobial activities in vitro and is effective against infections with antibiotic-resistant bacteria and fluconazole-resistant Candida albicans in animals. However, the mechanisms underlying these activities remain largely unclear. Since hLF1-11 is ineffective in vitro at physiological salt concentrations, we suggested modulation of the immune system as an additional mechanism of action of the peptide. We investigated whether hLF1-11 affects human monocyte-macrophage differentiation and determined the antimicrobial activities of the resulting macrophages. Monocytes were cultured for 7 days with GM-CSF in the presence of hLF1-11, control peptide, or saline for various intervals. At day 6, the cells were stimulated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or heat-killed C. albicans for 24 h. Thereafter, the levels of cytokines in the culture supernatants, the expression of pathogen recognition receptors, and the antimicrobial activities of these macrophages were determined. The results showed that a short exposure of monocytes to hLF1-11 during GM-CSF-driven differentiation is sufficient to direct differentiation of monocytes toward a macrophage subset characterized by both pro- and anti-inflammatory cytokine production and increased responsiveness to microbial structures. Moreover, these macrophages are highly effective against C. albicans and Staphylococcus aureus. In conclusion, hLF1-11 directs GM-CSF-driven differentiation of monocytes toward macrophages with enhanced effector functions.
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center (LUMC), C5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Anne M
authors.initials: AM
authors.lastname: van der Does
authors.forename: Sylvia J P
authors.initials: SJ
authors.lastname: Bogaards
authors.forename: Bep
authors.initials: B
authors.lastname: Ravensbergen
authors.forename: Henry
authors.initials: H
authors.lastname: Beekhuizen
authors.forename: Jaap T
authors.initials: JT
authors.lastname: van Dissel
authors.forename: Peter H
authors.initials: PH
authors.lastname: Nibbering
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007781:Lactoferrin; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects / Q000276:immunology
chemical_list: D000890:Anti-Infective Agents; D016207:Cytokines; D010446:Peptide Fragments; C466658:lactoferrin (1-11), human; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007781:Lactoferrin