The human cationic peptide LL-37 induces activation of the extracellular signal-regulated kinase and p38 kinase pathways in primary human monocytes.
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.
Department of Microbiology, University of British Columbia, Vancouver, British Columbia, Canada.
Dawn M E
DM
Bowdish
Donald J
DJ
Davidson
David P
DP
Speert
Robert E W
RE
Hancock
D023181:Antimicrobial Cationic Peptides / Q000097:blood / Q000502:physiology*; D054804:Cathelicidins; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D004789:Enzyme Activation / Q000276:immunology; D004847:Epithelial Cells / Q000201:enzymology; D019204:GTP-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000097:blood; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology; D036143:Receptor, EphA8 / Q000235:genetics; D014158:Transcription, Genetic / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D018925:Chemokines; D016209:Interleukin-8; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D036143:Receptor, EphA8; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins