sq-23377 and nodularin

Nodularin is a cyclic peptide produced by cyanobacteria. In the present study, the inhibitory effect of nodularin on T lymphocyte functions was demonstrated. Direct addition of nodularin to B6C3F1 mouse splenocyte cultures produced a concentration-dependent inhibition of the lymphoproliferative response to concanavalin A stimulation. Nodularin inhibited PMA plus ionomycin (Io)-induced IL-2 mRNA expression in murine splenocytes and thymocytes as determined by quantitative/competitive RT-PCR. To further characterize the mechanism for the transcriptional regulation of IL-2, the binding activity of transcription factors, NF-AT, AP-1, NF-kappaB, and Oct, was evaluated by electrophoretic mobility shift assays in mouse splenocytes. Nodularin reduced the NF-AT binding activity in PMA/Io-induced splenocytes, but no significant effect was observed on AP-1, NF-kappaB, or Oct binding activity. Nodularin also inhibited IL-4 mRNA expression in PMA/Io-stimulated murine splenocytes. These results suggest that T lymphocyte is a possible cellular target of nodularin, and the inhibitory effect of nodularin on T-cell specific transcription factor NF-AT induces T-cell dysfunction, which leads to a diminution in IL-2 and IL-4 gene transcription.

Topics: Animals; Bacterial Toxins; Binding, Competitive; Cells, Cultured; Concanavalin A; DNA-Binding Proteins; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Host Cell Factor C1; Interleukin-2; Interleukin-4; Ionomycin; Lymphocyte Activation; Mice; NF-kappa B; NFATC Transcription Factors; Nuclear Proteins; Octamer Transcription Factor-1; Peptides, Cyclic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spleen; T-Lymphocytes; Tetradecanoylphorbol Acetate; Thymus Gland; Transcription Factor AP-1; Transcription Factors