Transcription of IL-2 and IL-4 genes is not inhibited by cyclosporin A in competent T cells.
Cyclosporin A (CsA) inhibits T-cell proliferation primarily by blocking the transcription of several early activation genes, especially those of the important T-cell growth factors IL-2 and IL-4. This effect seems to be mediated through inhibition of the activity of the transcription factor NF-AT which is essential for IL-2 and probably for IL-4 gene transcription. However, once T cells are rendered "competent" to proliferate following a brief exposure to the phorbol ester, phorbol 12,13-dibutyrate (PDBu), and the calcium ionophore, ionomycin, CsA no longer inhibits cell cycle progression supported by the presence of PDBu alone. Here it is shown that transcription of the IL-2 and IL-4 genes occurs normally throughout this "progression" phase, even in the presence of CsA. However, further production of functional NF-AT, which began during the competence phase of the cell cycle, is inhibited. These data indicate that, although the primary initiation of transcription of IL-2 and IL-4 mRNA during induction of competence may be NF-AT-dependent and CsA-sensitive, the augmentation in the progression phase is both NF-AT-independent and CsA-resistant.
Terada
N
N
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Raymond and Beverly Sackler Foundation, Denver, Colorado 80224.
Or
R
R
Weinberg
K
K
Domenico
J
J
Lucas
J J
JJ
Gelfand
E W
EW
D001483:Base Sequence; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004261:DNA Replication; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D015847:Interleukin-4 / Q000235:genetics*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013936:Thymidine; D014158:Transcription, Genetic / Q000187:drug effects*
D007376:Interleukin-2; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D015847:Interleukin-4; D016572:Cyclosporine; D013936:Thymidine