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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.

Mechanism Responsible for T-Cell Antigen Receptor- and CD28- or Interleukin 1 (IL-1) Receptor-Initiated Regulation of IL-2 Gene Expression by NF-kappa B

Kimberly Kalli, Catherine Huntoon, Michael Bell, and David J. McKean*

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-kappa B sites. This study comparatively evaluates the mechanisms whereby signals initiated from the TCR and these two costimulatory receptors converge to synergistically increase NF-kappa B transcriptional activity. IL-1 alone stimulates an acute but transient NF-kappa B nuclear localization and a suboptimal NF-kappa B transcriptional 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 receptor-initiated synergistic NF-kappa B responses result from prolonging high rates of cytosolic Ikappa 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 complexes is not necessarily associated with long-term depletion of Ikappa Bbeta . 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-Ikappa Balpha complexes, which turn over rapidly due to the high rate of Ikappa Balpha degradation in the cytosol during the second phase of the response. In contrast, Ikappa Bbeta 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 Ikappa Bbeta . Cyclosporine (CsA), which inhibits stimulus-induced NF-kappa B transcriptional activity, selectively inhibits the stimulus-induced c-Rel nuclear localization and the rapid formation and degradation of c-Rel-Ikappa Balpha complexes in the cytosol. CsA also inhibits both the prolonged, high rate of Ikappa Balpha degradation and the lower level of Ikappa Bbeta 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-kappa B nuclear translocation.

* Corresponding author. Mailing address: Department of Immunology, Mayo Clinic, Rochester, MN 55905. Phone: (507) 284-8178. Fax: (507) 284-1637. E-mail: mckean.david{at}mayo.edu.

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.


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