Suppression of IL-2 and IL-4 gene expression by nodularin through the reduced NF-AT binding activity

Nodularin is a cyclic peptide produced by cyanobacteria. In the present stu dy, the inhibitory effect of nodularin on T lymphocyte functions was demons trated. Direct addition of nodularin to B6C3F1 mouse splenocyte cultures pr oduced a concentration-dependent inhibition of the lymphoproliferative resp onse to concanavalin A stimulation. Nodularin inhibited PMA plus ionomycin (Io)-induced IL-2 mRNA expression in murine splenocytes and thymocytes as d etermined by quantitative/competitive RT-PCR. To further characterize the m echanism for the transcriptional regulation of IL-2, the binding activity o f transcription factors, NF-AT, AP-1, NF-kappa B, and Oct, was evaluated by electrophoretic mobility shift assays in mouse splenocytes. Nodularin redu ced the NF-AT binding activity in PMA/Io-induced splenocytes, but no signif icant effect was observed on AP-1, NF-kappa B, or Oct binding activity. Nod ularin also inhibited IL-4 mRNA expression in PMA/Io-stimulated murine sple nocytes. These results suggest that T lymphocyte is a possible cellular tar get of nodularin, and the inhibitory effect of nodularin on T-cell specific transcription factor NF-AT induces T-cell dysfunction, which leads to a di minution in IL-2 and IL-4 gene transcription. (C) 2000 Elsevier Science Ire land Ltd. All rights reserved.