FK506 inhibits antigen receptor-mediated induction of c-rel in B and T lymphoid cells.
Stimulation of B and T cells via the antigen receptor, by phorbol ester or by phorbol ester and ionomycin, leads to nuclear translocation of the inducible transcription factor NF-kappa B, comprising the p50 and p65 rel-related polypeptides. In this report we show that c-rel is a component of the antigen receptor-induced kappa B binding proteins in both B and T cells. Whereas NF-kappa B can be induced by phorbol ester alone, optimal induction of c-rel requires stimulation by both phorbol ester and ionomycin, the dual signal that is necessary for proliferation of untransformed lymphocytes. Furthermore, c-rel induction is blocked by the immunosuppressive drug FK506 that is known to inhibit B and T cell activation. c-rel-dependent transactivation of the interleukin-2 receptor alpha chain (IL-2R alpha) promoter is augmented by coexpression of calcineurin, suggesting the involvement of a calcineurin-dependent intracellular pathway. Our results identify c-rel as a target of immunosuppressive agents and illustrate the similarity of activation pathways in both B and T cells.
Venkataraman
L
L
Rosenstiel Research Center, Brandeis University, Waltham, Massachusetts 02254-9110.
Burakoff
S J
SJ
Sen
R
R
D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000032:analysis / Q000502:physiology; D015759:Ionomycin / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000032:analysis / Q000502:physiology; D011090:Polyenes / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D020569:Proto-Oncogene Proteins c-rel; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000235:genetics; D020123:Sirolimus; D013601:T-Lymphocytes / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D002148:Calmodulin-Binding Proteins; D016328:NF-kappa B; D011090:Polyenes; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; D017472:Receptors, Interleukin-1; D015759:Ionomycin; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D013755:Tetradecanoylphorbol Acetate; D020123:Sirolimus; D016559:Tacrolimus