Structure-function relationship of the human antimicrobial peptide LL-37 and LL-37 fragments in the modulation of TLR responses.
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.
Molhoek
E Margo
EM
TNO Defense, Security and Safety, NL-2280AARijswijk, The Netherlands; Department of Parasitology, Leiden University Medical Center, NL-2333 ZA Leiden, The Netherlands. margo.molhoek@tno.nl
den Hertog
Alice L
AL
de Vries
Anne-Marij B C
AM
Nazmi
Kamran
K
Veerman
Enno C I
EC
Hartgers
Franca C
FC
Yazdanbakhsh
Maria
M
Bikker
Floris J
FJ
van der Kleij
Desiree
D
D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D054804:Cathelicidins; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D051193:Toll-Like Receptors / Q000819:agonists / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D008024:Ligands; D051193:Toll-Like Receptors