A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1 beta processing and release.
The release of IL-1 beta is a tightly controlled process that requires induced synthesis of the precursor pro-IL-1 beta and a second stimulus that initiates cleavage and secretion of mature IL-1 beta. Although ATP as a second stimulus potently promotes IL-1 beta maturation and release via P2X(7) receptor activation, millimolar ATP concentrations are needed. The human cathelicidin-derived peptide LL37 is a potent antimicrobial peptide produced predominantly by neutrophils and epithelial cells. In this study, we report that LL37 stimulation of LPS-primed monocytes leads to maturation and release of IL-1 beta via the P2X(7) receptor. LL37 induces a transient release of ATP, membrane permeability, caspase-1 activation, and IL-1 beta release without cell cytotoxicity. IL-1 beta release and cell permeability are suppressed by pretreatment with the P2X(7) inhibitors oxidized ATP, KN04, and KN62. In the presence of apyrase, which hydrolyzes ATP to AMP, the effect of LL37 was not altered, indicating that LL37 rather than autocrine ATP is responsible for the activation of the P2X(7) receptor. We conclude that endogenous LL37 may promote IL-1 beta processing and release via direct activation of P2X(7) receptors.
Elssner
Andreas
A
The Dorothy M. Davis Heart and Lung Research Institute and Pulmonary and Critical Care Division, Ohio State University, Columbus, OH 43210, USA.
Duncan
Michelle
M
Gavrilin
Mikhail
M
Wewers
Mark D
MD
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors / Q000502:physiology*; D001081:Apyrase / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D020170:Caspase 1 / Q000378:metabolism; D054804:Cathelicidins; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000276:immunology; D058919:Purinergic P2 Receptor Antagonists; D044042:Receptors, Formyl Peptide / Q000502:physiology; D044067:Receptors, Lipoxin / Q000502:physiology; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; C105101:FPR2 protein, human; D007375:Interleukin-1; D008070:Lipopolysaccharides; C546468:P2RX7 protein, human; D058919:Purinergic P2 Receptor Antagonists; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C065344:KN 04; C017199:2',3'-dialdehyde ATP; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000255:Adenosine Triphosphate; D020170:Caspase 1; D001081:Apyrase