Jh. Lai et Th. Tan, CD28 SIGNALING CAUSES A SUSTAINED DOWN-REGULATION OF I-KAPPA-B-ALPHA WHICH CAN BE PREVENTED BY THE IMMUNOSUPPRESSANT RAPAMYCIN, The Journal of biological chemistry, 269(48), 1994, pp. 30077-30080
CD28, an important T cell surface molecule, mediates a costimulatory s
ignal in the activation of T cell immune responses. CD28 signaling is
resistant to the immunosuppressant cyclosporin A (CsA) but sensitive t
o the immunosuppressant rapamycin. CD28 costimulation induces transcri
ption from the interleukin (IL)-2 promoter via the CD28 response eleme
nt. The levels of c-Rel, a CD28 response element-binding factor, were
found previously to be increased by CD28 costimulation. Therefore, we
focused our present study on the mechanism(s) of c-Rel up-regulation b
y CD28 signaling in Jurkat T cells. In this paper, we showed that CD28
costimulation accelerated the kinetics of nuclear translocation of c-
Rel. We showed that CD28 signaling, distinct from other stimuli such a
s phorbol 12-myristate 13-acetate, IL-1, and tumor necrosis factor-alp
ha, caused a sustained down regulation of the inhibitor I kappa B alph
a in Jurkat T cells. However, the levels of two other c-Rel inhibitors
, namely NFKB1 (p105) and NFKB2 (p100), were not affected. Remarkably,
the CD28-mediated down-regulation of I kappa B alpha was prevented by
rapamycin but not by CsA. The counter-regulation of I kappa B alpha b
y CD28 signaling and rapamycin observed in Jurkat T cells is also repr
oducible in primary T cells. In contrast, the phorbol 12-myristate 13-
acetate/ionomycin-mediated down-regulation of I kappa B alpha was prev
ented by CsA but not by rapamycin. Our data suggest that I kappa B alp
ha is the downstream target of both CD28 signaling and rapamycin; a co
ntinued down-regulation of I kappa B alpha by CD28 costimulation leads
to enhanced nuclear translocation of c-Rel, which in turn causes a su
stained up-regulation of IL-2 gene expression.