Cytokine-mediated Bax deficiency and consequent delayed neutrophil apoptosis: A general mechanism to accumulate effector cells in inflammation

Neutrophils are important effector cells in immunity to microorganisms, par ticularly bacteria. Here, we show that the process of neutrophil apoptosis is delayed in several inflammatory diseases, suggesting that this phenomeno n may represent a general feature contributing to the development of neutro philia, and, therefore, in many cases to host defense against infection. Th e delay of neutrophil apoptosis was associated with markedly reduced levels of Bar, a pro-apoptotic member of the Bcl-2 family. Such Bax-deficient cel ls were also observed upon stimulation of normal neutrophils with cytokines present at sites of neutrophilic inflammation, such as granulocyte and gra nulocyte-macrophage colony-stimulating factors, in vitro. Moreover, Bax-def icient neutrophils generated by using Bar antisense oligodeoxynucleotides d emonstrated delayed apoptosis, providing direct evidence for a role of Bar as a pro-apoptotic molecule in these cells. Interestingly, the Bar gene was reexpressed in Bax-deficient neutrophils under conditions of cytokine with drawal. Thus, both granulocyte expansion and the resolution of inflammation appear to be regulated by the expression of the Bar gene in neutrophils.