The human lactoferrin-derived peptide hLF1-11 primes monocytes for an enhanced TLR-mediated immune response.
Earlier we reported that the peptide corresponding to the first eleven N-terminal amino acids of human lactoferrin (hLF1-11) is active against multi-drug resistant pathogens in mice. The mechanisms underlying this anti-infective activity remain unclear. Since hLF1-11 is ineffective against pathogens at physiological salt concentrations and hLF1-11 directs differentiation of monocytes toward a macrophage subset with enhanced effector functions, we investigated the effects of hLF1-11 on human and murine monocytes. Results revealed that human and murine monocytes exposed for 1 h to hLF1-11 and then stimulated with the Toll-like receptor (TLR)-ligand LPS for 18 h, displayed enhanced cytokine and chemokine production as compared to control (peptide-treated) monocytes. We also found that expression of mRNA, cell-surface receptor expression, and NF-kappaB activation by hLF1-11-exposed human monocytes were enhanced as compared to control (peptide-treated) monocytes. Furthermore, the kinetics of the cytokine production was unchanged as mRNA levels and protein levels paralleled the enhanced response of hLF1-11-exposed monocytes to LPS. The cytokine production by human monocytes in response to TLR4, TLR5, and TLR7 stimulation, but not to TLR2 stimulation, was elevated by hLF1-11. In concordance, translocation of NF-kappaB subunits to the nucleus was enhanced in hLF1-11-exposed monocytes after TLR stimulation, except for TLR2, as compared to control (peptide-exposed) monocytes. In conclusion, monocytes were primed by hLF1-11 for an enhanced inflammatory response upon TLR4, TLR5, and TLR7 stimulation, but not TLR2 stimulation. Such effects of hLF1-11 on monocyte reactivity should be taken into account when considering the clinical development of this peptide for a therapeutic intervention in patients.
Department of Infectious Diseases, Leiden University Medical Center (LUMC), P.O. Box 9600, C5-P, 2300 RC, Leiden, The Netherlands.
Anne M
AM
van der Does
Sylvia J P
SJ
Bogaards
Luigi
L
Jonk
Marty
M
Wulferink
Markwin P
MP
Velders
Peter H
PH
Nibbering
D000818:Animals; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007700:Kinetics; D007781:Lactoferrin / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D051193:Toll-Like Receptors / Q000276:immunology*
D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; C466658:lactoferrin (1-11), human; D007781:Lactoferrin