Title
Structure-function relationship of the human antimicrobial peptide LL-37 and LL-37 fragments in the modulation of TLR responses
Author
TNO Defensie en Veiligheid
Molhoek, E.M.
den Hertog, A.L.
de Vries, A.M.B.C.
Nazmi, K.
Veerman, E.C.I.
Hartgers, F.C.
Yazdanbakhsh, M.
Bikker, F.J.
van der Kleij, D.
Publication year
2009
Abstract
Cathelicidins are effector molecules of the innate host defense system that establish an antimicrobial barrier at epithelial interfaces. The human cathelicidin LL-37, in addition to its antimicrobial activity, also exhibits immunomodulatory effects, such as inhibition of pro-inflammatory responses to bacterial LPS in human monocytic cells. In this report, we demonstrate that LL-37 almost completely prevents the pro-inflammatory cytokine release by human peripheral blood mononuclear cells (PBMCs) following stimulation with Toll-like receptor (TLR)4 and TLR2/1 agonists while leaving TLR2/6, TLR5, TLR7 and TLR8 responses unchanged. Modulation of the TLR response by LL-37 occurred at least partly through the MAP kinase pathway via inhibition of p38 phosphorylation. By using an LL-37 library with overlapping sequences, we identified the mid-region of LL-37, comprising amino acids 13–31, as the active domain for the modulation of TLR responses. The mechanism of immunomodulation of LL-37 and LL-37 fragments is lipopoly-saccharide binding. Correlations between the capacity of LL-37 fragments to modulate TLR responses and their physico-chemical properties revealed that cationicity and hydrophobicity are essential for the modulation of LL-37-mediated TLR responses.
Subject
Cathelicidins
Immunomodulation
MAP kinases
Physico-chemical properties
Bacterium lipopolysaccharide
Cathelicidin antimicrobial peptide LL 37
Cytokine
Mitogen activated protein kinase
Mitogen activated protein kinase p38
Toll like receptor
Toll like receptor 1
Toll like receptor 2
Toll like receptor 4
Toll like receptor 5
Toll like receptor 6
Toll like receptor 7
Toll like receptor 8
Antiinflammatory activity
Antimicrobial activity
Article
Cytokine release
Human
Human cell
Hydrophobicity
Immunomodulation
Peripheral blood mononuclear cell
Priority journal
Protein phosphorylation
Structure activity relation
Amino Acid Sequence
Antimicrobial Cationic Peptides
Cells, Cultured
Chromatography, High Pressure Liquid
Circular Dichroism
Humans
Ligands
Molecular Sequence Data
Signal Transduction
Structure-Activity Relationship
Toll-Like Receptors
Bacteria (microorganisms)
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DOI
https://doi.org/10.1515/bc.2009.037
TNO identifier
90032
ISSN
1431-6730
Source
Biological Chemistry, 390 (390), 295-303
Document type
article