An antimicrobial cathelicidin peptide, human CAP18/LL-37, suppresses neutrophil apoptosis via the activation of formyl-peptide receptor-like 1 and P2X7.
Peptide antibiotics possess the potent antimicrobial activities against invading microorganisms and contribute to the innate host defense. An antibacterial cathelicidin, human cationic antibacterial protein of 18 kDa/LL-37, not only exhibits potent bactericidal activities against Gram-negative and Gram-positive bacteria, but also functions as a chemoattractant for immune cells, including neutrophils. During bacterial infections, the life span of neutrophils is regulated by various pathogen- and host-derived substances. In this study, to further evaluate the role of LL-37 in innate immunity, we investigated the action of LL-37 on neutrophil apoptosis. Neutrophil apoptosis was assessed using human blood neutrophils based on the morphological changes. Of note, LL-37 dose dependently (0.01-5 microg/ml) suppressed neutrophil apoptosis, accompanied with the phosphorylation of ERK-1/2, expression of Bcl-x(L) (an antiapoptotic protein), and inhibition of caspase 3 activity. Interestingly, LL-37-induced suppression of neutrophil apoptosis was attenuated by the antagonists for formyl-peptide receptor-like 1 (FPRL1) and P2X7 nucleotide receptor. Of importance, the agonists for FPRL1 and P2X7 apparently suppressed neutrophil apoptosis. Collectively, these observations indicate that LL-37 cannot only kill bacteria, but also modulate (suppress) neutrophil apoptosis via the activation of FPRL1 and P2X7 in bacterial infections. Suppression of neutrophil apoptosis results in the prolongation of their life span, and may be advantageous for host defense against bacterial invasion.
Department of Host Defense and Biochemical Research, Juntendo University, School of Medicine, Tokyo, Japan. nagaokai@med.juntendo.ac.jp
Isao
I
Nagaoka
Hiroshi
H
Tamura
Michimasa
M
Hirata
D000255:Adenosine Triphosphate / Q000502:physiology; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000097:blood / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000097:blood / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D054804:Cathelicidins; D016207:Cytokines / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D044042:Receptors, Formyl Peptide / Q000378:metabolism* / Q000502:physiology; D044067:Receptors, Lipoxin / Q000378:metabolism* / Q000502:physiology; D018048:Receptors, Purinergic P2 / Q000378:metabolism* / Q000502:physiology; D058486:Receptors, Purinergic P2X7; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C494811:BCL2L1 protein, human; D054804:Cathelicidins; D016207:Cytokines; C105101:FPR2 protein, human; C546468:P2RX7 protein, human; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D051020:bcl-X Protein; D000255:Adenosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases