Cyclosporin A enhances the calcium-dependent induction of AP-1 complex and c-fos mRNA in a T cell lymphoma.

The immunosuppressant cyclosporin A (CsA) exerts its pharmacologic actions by inhibiting calcineurin function. Here, we investigated the effect of CsA on the DNA-binding activity of the transcription factor, AP-1, in YAC-1 cells. We found that elevation of intracellular Ca2+ by ionomycin increased AP-1 DNA-binding activity in these cells. CsA treatment upregulated the ionomycin-induced, but not the basal AP-1 DNA-binding activity. In contrast, a CsA analog, MeVal4CsA, that does not inhibit calcineurin, failed to enhance ionomycin-induced AP-1 DNA-binding activity. This activity was shown to involve c-Fos, c-Jun and JunB. CsA consistently augmented ionomycin-induced c-fos mRNA expression and more variably that of JunB. Therefore, calcineurin negatively regulates Ca(2+)-stimulated AP-1 activity principally at the c-fos induction level. By inhibiting calcineurin, CsA shifts the balance between positive and negative AP-1 regulation. Since AP-1 controls the transcription of many genes, this finding may have implications for both the immunosuppressive and toxic effects of CsA.