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.