Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37

J Immunol. 2006 Feb 15;176(4):2455-64. doi: 10.4049/jimmunol.176.4.2455.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimicrobial Cationic Peptides / metabolism
  • Antimicrobial Cationic Peptides / pharmacology*
  • Cell Line
  • Gene Expression Profiling
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Kinetics
  • Lipopolysaccharides / pharmacology
  • NF-kappa B / metabolism
  • Protein Subunits / metabolism
  • Protein Transport
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism*
  • Transcription, Genetic / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antimicrobial Cationic Peptides
  • Lipopolysaccharides
  • NF-kappa B
  • Protein Subunits
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • ropocamptide