MECHANISM RESPONSIBLE FOR T-CELL ANTIGEN RECEPTOR-INITIATED AND CD28-INITIATED OR INTERLEUKIN-1 (IL-1) RECEPTOR-INITIATED REGULATION OF IL-2 GENE-EXPRESSION BY NF-KAPPA-B

Initiation of the T-helper lymphocyte activation program is regulated through the T-cell receptor (TCR) and costimulatory receptors, Analysi s of TCR and either anti-CD28- or interleukin 1 (IL-1) mediated activa tion of the IL-2 promoter shows that costimulatory signals augment pro moter activity through NF-kappa B sites. This study comparatively eval uates the mechanisms whereby signals initiated from the TCR and these two costimulatory receptors converge to synergistically increase NF-ka ppa B transcriptional activity, IL-1 alone stimulates an acute but tra nsient NF-kappa B nuclear localization and a suboptimal NF-kappa B tra nscriptional response. In contrast, anti-CD3-anti-CD28 or anti-CD3-IL- 1 synergistically stimulate prolonged NF-kappa B nuclear localization and NF-kappa B mediated transcription. Both TCR-and costimulatory rece ptor-initiated synergistic NF-kappa B responses result from prolonging high rates of cytosolic I kappa B degradation during the second phase of the biphasic NF-kappa B nuclear localization. However, in contrast to previous reports, prolonged nuclear localization of NF-kappa B com plexes is not necessarily associated with long-term depletion of I kap pa B beta. In response to either costimulus, c-Rel selectively translo cated to the nucleus as a result of induced c-Rel expression and the c ontinued production of c-Rel-I kappa B alpha complexes, which turn ove r rapidly due to the high rate of I kappa B alpha degradation in the c ytosol during the second phase of the response, In contrast, I kappa B beta is nearly completely degraded during the acute response to eithe r IL-1 or anti-CD3-IL-1 while anti-CD3-anti-CD28 stimulates only a par tial reduction (35 to 40%) in cytosolic I kappa B beta, Cyclosporine ( CsA), which inhibits stimulus-induced NF-kappa B transcriptional activ ity, selectively inhibits the stimulus-induced c-Rel nuclear localizat ion and the rapid formation and degradation of c-Rel-I kappa B alpha c omplexes in the cytosol, CsA also inhibits both the prolonged, high ra te of I kappa B alpha degradation and the lower level of I kappa B bet a turnover during the second phase of the activation response, Togethe r, 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-kappa B nuclear translocation.