Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37.
The sole human cathelicidin peptide, LL-37, has been demonstrated to protect animals against endotoxemia/sepsis. Low, physiological concentrations of LL-37 (< or =1 microg/ml) were able to modulate inflammatory responses by inhibiting the release of the proinflammatory cytokine TNF-alpha in LPS-stimulated human monocytic cells. Microarray studies established a temporal transcriptional profile and identified differentially expressed genes in LPS-stimulated monocytes in the presence or absence of LL-37. LL-37 significantly inhibited the expression of specific proinflammatory genes up-regulated by NF-kappaB in the presence of LPS, including NFkappaB1 (p105/p50) and TNF-alpha-induced protein 2 (TNFAIP2). In contrast, LL-37 did not significantly inhibit LPS-induced genes that antagonize inflammation, such as TNF-alpha-induced protein 3 (TNFAIP3) and the NF-kappaB inhibitor, NFkappaBIA, or certain chemokine genes that are classically considered proinflammatory. Nuclear translocation, in LPS-treated cells, of the NF-kappaB subunits p50 and p65 was reduced > or =50% in the presence of LL-37, demonstrating that the peptide altered gene expression in part by acting directly on the TLR-to-NF-kappaB pathway. LL-37 almost completely prevented the release of TNF-alpha and other cytokines by human PBMC following stimulation with LPS and other TLR2/4 and TLR9 agonists, but not with cytokines TNF-alpha or IL-1beta. Biochemical and inhibitor studies were consistent with a model whereby LL-37 modulated the inflammatory response to LPS/endotoxin and other agonists of TLR by a complex mechanism involving multiple points of intervention. We propose that the natural human host defense peptide LL-37 plays roles in the delicate balancing of inflammatory responses in homeostasis as well as in combating sepsis induced by certain TLR agonists.
Mookherjee
Neeloffer
N
Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
Brown
Kelly L
KL
Bowdish
Dawn M E
DM
Doria
Silvana
S
Falsafi
Reza
R
Hokamp
Karsten
K
Roche
Fiona M
FM
Mu
Ruixia
R
Doho
Gregory H
GH
Pistolic
Jelena
J
Powers
Jon-Paul
JP
Bryan
Jenny
J
Brinkman
Fiona S L
FS
Hancock
Robert E W
RE
D023181:Antimicrobial Cationic Peptides / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D008070:Lipopolysaccharides; D016328:NF-kappa B; D021122:Protein Subunits; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D054804:Cathelicidins