The human cationic peptide LL-37 induces activation of the extracellular signal-regulated kinase and p38 kinase pathways in primary human monocytes

Dawn M E Bowdish, Donald J Davidson, David P Speert, Robert E W Hancock

Research output: Contribution to journalArticlepeer-review

Abstract

LL-37 is a cationic peptide that is found in the granules of neutrophils and is secreted by epithelial cells from a variety of tissues. Levels of LL-37 in vivo increase upon infection, and its production and secretion are increased upon stimulation with proinflammatory mediators. It has been postulated that LL-37 modulates the immune response by interacting with the effector cells of innate immunity; however, the mechanism of this interaction is unknown. LL-37 induced phosphorylation and activation of the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) and p38, in human peripheral blood-derived monocytes and a human bronchial epithelial cell line, but not in B or T lymphocytes. Phosphorylation was not dependent on the G protein-coupled formyl peptide-like receptor 1, which was previously proposed to be the receptor for LL-37-induced chemotaxis on human monocytes and T cells. Activation of ERK1/2 and p38 was markedly increased by the presence of GM-CSF, but not M-CSF. Exposure to LL-37 also led to the activation of Elk-1, a transcription factor that is downstream of and activated by phosphorylated ERK1/2, the up-regulation of various Elk-1-controlled genes, and the transcription and secretion of IL-8. Inhibition of either p38 or ERK1/2 kinases led to a reduction in LL-37-induced IL-8 secretion and inhibition of the transcription of various chemokine genes. The ability of LL-37 to signal through these pathways has broad implications in immunity, monocyte activation, proliferation, and differentiation.

Original languageEnglish
Pages (from-to)3758-65
Number of pages8
JournalJournal of Immunology
Volume172
Issue number6
Publication statusPublished - 15 Mar 2004

Keywords

  • Antimicrobial Cationic Peptides
  • Cathelicidins
  • Cells, Cultured
  • Chemokines
  • Cytotoxicity, Immunologic
  • Dose-Response Relationship, Immunologic
  • Drug Synergism
  • Enzyme Activation
  • Epithelial Cells
  • GTP-Binding Proteins
  • Gene Expression Regulation
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Humans
  • Interleukin-8
  • MAP Kinase Signaling System
  • Macrophage Activation
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Monocytes
  • Receptor, EphA8
  • Transcription, Genetic
  • p38 Mitogen-Activated Protein Kinases

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