The Bcl-2 gene is differentially regulated by IL-2 and IL-4: role of the transcription factor NF-AT.
The murine TS1alphabeta T cell line expresses the anti-apoptotic protein Bcl-2 upon IL-2 stimulation, whereas IL-4-mediated growth of this cell line proceeds in the absence of Bcl-2 expression. In addition, IL-4 stimulation inhibits Bcl-2 expression and modulates its mRNA level. IL-2-induced DNA binding activity for these transcription factors is sensitive to phosphatidylinositol 3 kinase inhibitor wortmannin and to Rho inhibitor Clostridium difficile toxin B, which inhibit IL-2-induced Bcl-2 expression. NF-AT transcription factor appears to be the most important in the control Bcl-2 expression, since inhibition of the calcium-calmodulin-dependent phosphatase calcineurin, which regulates NF-AT activity, downregulates Bcl-2 expression in IL-2-stimulated cells. Constitutive expression of this phosphatase also upregulates Bcl-2 expression in IL-4-stimulated cells. In addition, a dominant negative NF-AT expression vector downregulates Bcl-2 expression in IL-2-stimulated cells. These results suggest that IL-2 induction of Bcl-2 expression may be directly or indirectly mediated by NF-AT.
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Universidad Autónoma, Madrid, Spain.
J
J
Gómez
C
C
Martínez-A
A
A
González
A
A
García
A
A
Rebollo
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation; D000077191:Wortmannin
D000730:Androstadienes; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C031815:toxB protein, Clostridium difficile; D015847:Interleukin-4; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus; D000077191:Wortmannin