Mol Cell Biol, June 1998, p. 3140-3148, Vol. 18, No. 6
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
B
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905
Received 19 September 1997/Returned for modification 11 November 1997/Accepted 10 March 1998
Initiation of the T-helper lymphocyte activation program is
regulated through the T-cell receptor (TCR) and costimulatory receptors. Analysis of TCR and either anti-CD28- or interleukin 1 (IL-1)-mediated activation of the IL-2 promoter shows that
costimulatory signals augment promoter activity through NF-
B sites.
This study comparatively evaluates the mechanisms whereby signals
initiated from the TCR and these two costimulatory receptors converge
to synergistically increase NF-
B transcriptional activity. IL-1 alone stimulates an acute but transient NF-
B nuclear localization and a suboptimal NF-
B transcriptional response. In contrast, anti-CD3-anti-CD28 or anti-CD3-IL-1 synergistically stimulate prolonged NF-
B nuclear localization and NF-
B-mediated
transcription. Both TCR- and costimulatory receptor-initiated
synergistic NF-
B responses result from prolonging high rates of
cytosolic I
B degradation during the second phase of the biphasic
NF-
B nuclear localization. However, in contrast to previous reports,
prolonged nuclear localization of NF-
B complexes is not necessarily
associated with long-term depletion of I
B
. In response to either
costimulus, c-Rel selectively translocated to the nucleus as a result
of induced c-Rel expression and the continued production of
c-Rel-I
B
complexes, which turn over rapidly due to the high rate
of I
B
degradation in the cytosol during the second phase of the
response. In contrast, I
B
is nearly completely degraded during
the acute response to either IL-1 or anti-CD3-IL-1 while
anti-CD3-anti-CD28 stimulates only a partial reduction (35 to 40%) in
cytosolic I
B
. Cyclosporine (CsA), which inhibits stimulus-induced
NF-
B transcriptional activity, selectively inhibits the
stimulus-induced c-Rel nuclear localization and the rapid formation and
degradation of c-Rel-I
B
complexes in the cytosol. CsA also
inhibits both the prolonged, high rate of I
B
degradation and the
lower level of I
B
turnover during the second phase of the
activation response. Together, these results suggest a mechanism by
which signals from the T-cell antigen receptor and either CD28 or IL-1
synergistically regulate IL-2 gene transcription by modulating NF-
B
nuclear translocation.
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