Sanglifehrin A, a novel cyclophilin-binding immunosuppressant, inhibits IL-2-dependent T cell proliferation at the G(1) phase of the cell cycle

Sanglifehrin A (SFA) is a novel immunosuppressive natural product that bind s to cyclophilin but is structurally distinct from cyclosporin A (CsA). We have investigated the cellular and molecular mechanisms of the action of SF A in T lymphocytes. We show that SFA inhibits T cell proliferation induced by IL-2 with an IC50 of 200 nM. Distinct from CsA, which also binds to cycl ophilin, SFA does not affect calcium-dependent IL-2 production, although SF A enhanced IL-2 gene transcription in the same cells. SFA blocks T cell pro liferation induced by IL-2 in G, with no appreciable effect on IL-2 recepto r expression in a manner similar to that of the immunosuppressant rapamycin . Unlike rapamycin, however, SFA has no effect on the phosphorylation or en zymatic activity of p7(s6k) kinase, distinguishing SFA from rapamycin in th eir mode of action. SFA inhibits hyperphosphorylation of Rb and the activit y of cyclin E-cyclin-dependent kinase 2 on IL-2 signaling. These results su ggest that SFA has a novel mode of action in comparison with CsA, FK506, an d rapamycin, and that its use as a molecular probe may lead to the discover y of a novel target involved in T cell activation.