Acceleration of human neutrophil apoptosis by TRAIL.
Neutrophil granulocytes have a short lifespan, with their survival limited by a constitutive program of apoptosis. Acceleration of neutrophil apoptosis following ligation of the Fas death receptor is well-documented and TNF-alpha also has a transient proapoptotic effect. We have studied the role of the death receptor ligand TRAIL in human neutrophils. We identified the presence of mRNAs for TRAIL, TRAIL-R2, and TRAIL-R3, and cell surface expression of TRAIL-R2 and -R3 in neutrophil populations. Neutrophil apoptosis is specifically accelerated by exposure to a leucine zipper-tagged form of TRAIL, which mimics cell surface TRAIL. Using blocking Abs to TRAIL receptors, specifically TRAIL-R2, and a TRAIL-R1:FcR fusion protein, we have excluded a role for TRAIL in regulating constitutive neutrophil apoptosis. No additional proapoptotic effect of leucine zipper TRAIL was identified following TRAIL treatment of neutrophils in the presence of gliotoxin, an inhibitor of NF-kappaB, suggesting TRAIL does not activate NF-kappaB in human neutrophils. TRAIL treatment of human neutrophils did not induce a chemotactic response. The susceptibility of neutrophils to TRAIL-mediated apoptosis suggests a role for TRAIL in the regulation of inflammation and may provide a mechanism for clearance of neutrophils from sites of inflammation.
Renshaw
Stephen A
SA
Respiratory Medicine Unit, Section of Functional Genomics, Division of Genomic Medicine, University of Sheffield, Royal Hallamshire Hospital, United Kingdom.
Parmar
Jasvir S
JS
Singleton
Vanessa
V
Rowe
Sarah J
SJ
Dockrell
David H
DH
Dower
Steven K
SK
Bingle
Colin D
CD
Chilvers
Edwin R
ER
Whyte
Moira K B
MK
D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D058851:GPI-Linked Proteins; D006801:Humans; D016350:Leucine Zippers / Q000276:immunology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D058851:GPI-Linked Proteins; C448905:LZ-TRAIL protein, recombinant; D008024:Ligands; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C108661:TNFRSF10C protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor