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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3683-3691
IMMUNOBIOLOGY
Constitutive nuclear factor- B activity preserves homeostasis
of quiescent mature lymphocytes and granulocytes by controlling
the expression of distinct Bcl-2 family proteins
Fabrice Bureau,
Alain Vanderplasschen,
Fabrice Jaspar,
Frédéric Minner,
Paul-Pierre Pastoret,
Marie-Paule Merville,
Vincent Bours, and
Pierre Lekeux
From the Department of Veterinary Physiology,
Department of Parasitic and Infectious Diseases, and Department of
Medical Chemistry and Medical Oncology, University of Liège,
Belgium.
Constitutive nuclear factor kappaB (NF- B) activity protects
quiescent mature immune cells from spontaneous apoptosis. Here, we
examined whether NF-B exerts its antiapoptotic function in these
cells through the control of Bcl-2 family proteins. Specific pharmacologic inhibitors of NF-B were used to achieve total NF-B inactivation in quiescent human blood lymphocytes, granulocytes, and
monocytes. NF-B 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-xL and Bcl-2, respectively. By contrast, granulocyte
apoptosis was fast and accompanied by a rapid cellular accumulation of
Bcl-xS, the proapoptotic Bcl-x isoform that is generated
from alternative splicing of the bcl-x pre-mRNA. Finally,
antisense bcl-xL 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-B 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-B maintains
defense integrity.
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