S. Patil et al., Smad7 is induced by CD40 and protects WEHI 231 B-lymphocytes from transforming growth factor-beta-induced growth inhibition and apoptosis, J BIOL CHEM, 275(49), 2000, pp. 38363-38370
Transforming growth factor-beta (TGF-beta) is a potent inducer of apoptosis
in B-lymphocytes and is essential for immune regulation and maintenance of
self-tolerance, Here we show that concomitant signaling through CD40 susta
ins proliferation and rescues the premature B cell line WEHI 231 from both
TGF-beta -induced and anti-IgM-induced apoptosis. The anti-apoptotic effect
of CD40 is associated with the transcriptional activation of the inhibitor
y Smad7 protein. The transactivation of Smad7 by CD40 is NF kappaB-dependen
t in that pharmacological inhibitors of this pathway, N-tosyl-L-phenylalani
ne chloromethyl ketone and pyrrolidine dithiocarbamate, abrogate CD40-induc
ed Smad7 expression. Ectopic overexpression of Smad7 inhibited Smad2 activa
tion, TGF-beta -mediated growth inhibition, and apoptosis in WEHI 231 cells
. Consistent with this result, dominant negative interference with Smad2 an
d Smad3 function also inhibited TGF-beta -induced apoptosis. The inhibitory
effects of Smad7 overexpression were specific to TGF-beta -induced apoptos
is and were without effect on anti-IgM-induced cell death. These results su
ggest a mechanism of suppression of TGF-beta -induced apoptosis by CD40, me
diated through activation of NF-kappaB and, consequently, induction of Smad
7 expression.