Constitutive nuclear factor-kappa B activity preserves homeostasis of quiescent mature lymphocytes and granulocytes by controlling the expression of distinct Bcl-2 family proteins

Constitutive nuclear factor kappaB (NFkappaB) activity protects quiescent mature Immune cells from spontaneous apoptosis. Here, we examined whether NF-kappaB exerts its antiapoptotic function in these cells through the control of Bcl-2 family proteins. Specific pharmacologic inhibitors of NF-kappaB were used to achieve total NF-kappaB inactivation In quiescent human blood lymphocytes, granulocytes, and monocytes. NF-kappaB inhibition induced drastic lymphocyte and granulocyte apoptosis, but only moderate monocyte apoptosis. T- and B-cell apoptosis was slow and associated with a gradual down-regulation of the prosurvival Bcl-2 family proteins Bcl-X-L and BcI-2, respectively. By contrast, granulocyte apoptosis was fast and accompanied by a rapid cellular accumulation of Bcl-x(s), the proapoptotic Bcl-x isoform that is generated from alternative splicing of the bcl-x pre-mRNA. Finally, antisense bci-x(L) and bcl-2 knockdown in T and B cells, respectively, and induction of Bcl-xs expression in granulocytes through antisense oligonucleotide-mediated redirection of bcl-x pre-mRNA splicing were sufficient to induce significant apoptosis in these cells. Taken together, these results reveal that basal NF-kappaB activity preserves homeostasis of quiescent mature lymphocytes and granulocytes through regulation of distinct members of the Bcl-2 family. This study sheds light on the constitutive mechanisms by which NF-kappaB maintains defense integrity. (C) 2002 by The American Society of Hematology