Bcl-Xl- and Bax-alpha-mediated regulation of apoptosis of human neutrophils via caspase-3.
In this study, a mechanism is reported which determines the lifetime of polymorphonuclear neutrophils (PMN). In human PMN freshly isolated from the circulation, expression of bcl-Xl, bax-alpha, and bak, members of the bcl-2 family of apoptosis-associated genes, was found using the reverse transcription-polymerase chain reaction technique. In contrast, no expression of bcl-2 was seen in PMN, whereas the myeloid cell line HL-60 was positive for bcl-2 mRNA. Two gene products, Bcl-Xl and Bax-alpha, which are known to function as the regulatory machinery of programmed cell death (apoptosis), were detected at the protein level in PMN. Moreover, differential expression of these proteins was found upon induction or prevention of apoptosis by cytokines: Whereas induction of apoptosis by tumor necrosis factor-alpha was associated with a reduction of expression of the anti-apoptotic Bcl-Xl protein, prevention of apoptosis by granulocyte-macrophage colony-stimulating factor led to a downregulation of expression of the death-promoting Bax-alpha protein. This shift of balance of anti- and pro-apoptotic proteins was found to control caspase-3 activity which, in turn, downregulated Bcl-Xl expression in PMN undergoing apoptosis. Thus, cytokines can affect the ratio of Bax-alpha/Bcl-Xl expression in human PMN and modulate the subsequent activity of caspase-3, which functions as executer of the programmed cell death and may promote apoptosis by a positive feed-forward mechanism that downregulates Bcl-Xl.
Weinmann
P
P
Department of Physiology, Freie Universität, Berlin, Germany.
Gaehtgens
P
P
Walzog
B
B
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000097:blood*; D002478:Cells, Cultured; D003374:Coumarins / Q000494:pharmacology; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000097:blood / Q000235:genetics*; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494826:BAX protein, human; C494811:BCL2L1 protein, human; D003374:Coumarins; D009842:Oligopeptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C106566:benzyloxycarbonyl-aspartyl-glutamyl-valyl-aspartyl-7-amino-4-trifluoromethylcoumarin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases