Journal
INFLAMMATION
Volume 34, Issue 5, Pages 412-425Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10753-010-9248-6
Keywords
LL-37; cathelicidin; triggering receptor expressed on myeloid cells 1 (TREM-1); lipopolysaccharide; inflammation
Categories
Funding
- Canadian Institutes for Health Research
- Foundation for the National Institutes of Health
- Bill and Melinda Gates Foundation
- Grand Challenges in Global Health Initiative
- Michael Smith Foundation for Health Research
- Canada Research Chair
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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.
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