Cathelicidin peptide LL-37 modulates TREM-1 expression and inflammatory responses to microbial compounds.
Inflammatory diseases remain an important cause of morbidity and mortality. Cathelicidins are immunomodulatory and antimicrobial peptides with potent anti-endotoxic properties. Although the effects of the human cathelicidin LL-37 on cellular responses to Toll-like receptor (TLR) ligands have been investigated, its effects on responses to other pro-inflammatory stimuli have not been well studied. Triggering receptor expressed on myeloid cells (TREM-1) acts to amplify inflammatory responses and plays important roles in the pathogenesis of endotoxemia. In this work, the effects of LL-37 on responses to TREM-1 stimulation, alone and in the presence of a range of microbial compounds, were analyzed. It was shown that in peripheral blood mononuclear cells LL-37 strongly suppressed synergistic responses to TREM-1 and TLR4 stimulation, partly through the inhibition of TREM-1 expression on monocytes; similar effects were observed using the TLR2 ligand lipoteichoic acid. In contrast, LL-37 stimulated TREM-1 upregulation by peptidoglycan (PGN, TLR2 ligand that is also recognized via nucleotide-binding oligomerization domain containing 2 after fragmentation and intracellular uptake), as well as the responses to combined TREM-1 and PGN stimulation, possibly via the p38 mitogen-activated protein kinase pathway. LL-37 did not affect TREM-1-induced neutrophil degranulation or the production of reactive oxygen species and interleukin-8 by neutrophils. These findings provide further insight into the roles of LL-37 during inflammation and may have implications for its in vivo immunomodulatory properties and for the design of synthetic cathelicidin derivatives as anti-inflammatory and anti-endotoxic molecules.
Amatngalim
Gimano D
GD
Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, 2259 Lower Mall Research Station, Vancouver, V6T 1Z4, Canada.
Nijnik
Anastasia
A
Hiemstra
Pieter S
PS
Hancock
Robert E W
RE
D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D015550:Cell Degranulation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D010457:Peptidoglycan / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011971:Receptors, Immunologic / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010457:Peptidoglycan; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; C495345:TLR4 protein, human; C408842:TREM1 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D054804:Cathelicidins
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