title: CD28 signaling causes a sustained down-regulation of I kappa B alpha which can be prevented by the immunosuppressant rapamycin.
abstract: CD28, an important T cell surface molecule, mediates a costimulatory signal in the activation of T cell immune responses. CD28 signaling is resistant to the immunosuppressant cyclosporin A (CsA) but sensitive to the immunosuppressant rapamycin. CD28 costimulation induces transcription from the interleukin (IL)-2 promoter via the CD28 response element. 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 by 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 as phorbol 12-myristate 13-acetate, IL-1, and tumor necrosis factor-alpha, caused a sustained down-regulation of the inhibitor I kappa B alpha 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 by CD28 signaling and rapamycin observed in Jurkat T cells is also reproducible in primary T cells. In contrast, the phorbol 12-myristate 13-acetate/ionomycin-mediated down-regulation of I kappa B alpha was prevented by CsA but not by rapamycin. Our data suggest that I kappa B alpha is the down-stream target of both CD28 signaling and rapamycin; a continued down-regulation of I kappa B alpha by CD28 costimulation leads to enhanced nuclear translocation of c-Rel, which in turn causes a sustained up-regulation of IL-2 gene expression.
authors.affiliation: Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: J H
authors.initials: JH
authors.lastname: Lai
authors.forename: T H
authors.initials: TH
authors.lastname: Tan
mesh_terms: D018106:CD28 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000302:isolation & purification; D006801:Humans; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011090:Polyenes / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D020569:Proto-Oncogene Proteins c-rel; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D018106:CD28 Antigens; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011090:Polyenes; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha; D016572:Cyclosporine; D013755:Tetradecanoylphorbol Acetate; D020123:Sirolimus