Bcl-X-I- 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 pol ymorphonuclear neutrophils (PMN). In human PMM freshly isolated from the ci rculation, expression of bcl-X-I, bax-alpha, and bak, members of the bcl-2 family of apoptosis-associated genes, was found using the reverse transcrip tion-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 bc l-2 mRNA. Two gene products, Bcl-X-I and Bax-alpha, which are known to func tion 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 cyto kines: Whereas induction of apoptosis by tumor necrosis factor-alpha was as sociated with a reduction of expression of the anti-apoptotic Bcl-X-I prote in, prevention of apoptosis by granulocyte-macrophage colony-stimulating fa ctor led to a downregulation of expression of the death-promoting Bax-alpha protein. This shift of balance of anti- and pro-apoptotic proteins was fou nd to control caspase-3 activity which, in turn, downregulated Bcl-X-I expr ession in PMN undergoing apoptosis. Thus, cytokines can affect the ratio of Bax-alpha/Bcl-X-I expression in human PMN and modulate the subsequent acti vity of caspase-3, which functions as executer of the programmed cell death and may promote apoptosis by a positive feed-forward mechanism that downre gulates Bcl-X-I. (C) 1999 by The American Society of Hematology.