Inhibition of spontaneous neutrophil apoptosis by parabutoporin acts independently of NADPH oxidase inhibition but by lipid raft-dependent stimulation of Akt.
Neutrophil cell death plays a crucial role in neutrophil homeostasis and the resolution of inflammation. The superoxide-producing NADPH oxidase is involved in pathogen degradation and subsequent activation of cell death programs. Neutrophils from patients with chronic granulomatous disease, who have a deficient NADPH oxidase activity, have been demonstrated previously to have a prolonged lifespan, suggesting that a basal NADPH oxidase activity also regulates spontaneous neutrophil turnover. The NADPH oxidase inhibitor parabutoporin (PP) does delay spontaneous apoptosis, but this effect is completely independent of NADPH oxidase inhibition. Instead, the prosurvival effect of PP depends on activation of protein kinase B/Akt via lipid raft signaling. Disruption of lipid rafts abrogates the prosurvival effect without interfering with NADPH oxidase activity. Furthermore, we cannot detect a different rate of spontaneous apoptosis between normal and NADPH oxidase-deficient neutrophils, arguing against a role of NADPH oxidase in spontaneous neutrophil apoptosis.
Remijsen
Quinten
Q
Department of Medicine, Laboratory of Biochemistry, K.U.L. Campus Kortrijk, E. Sabbelaan 53, Kortrijk, Belgium.
Vanden Berghe
Tom
T
Parthoens
Eef
E
Asselbergh
Bob
B
Vandenabeele
Peter
P
Willems
Jean
J
D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D007700:Kinetics; D021962:Membrane Microdomains / Q000502:physiology*; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000166:cytology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012604:Scorpion Venoms / Q000494:pharmacology*
D023181:Antimicrobial Cationic Peptides; D012604:Scorpion Venoms; C496148:parabutoporin, Parabuthus schlechteri; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; D051057:Proto-Oncogene Proteins c-akt