Sanglifehrin A, a novel cyclophilin-binding immunosuppressant, inhibits IL-2-dependent T cell proliferation at the G1 phase of the cell cycle.
Sanglifehrin A (SFA) is a novel immunosuppressive natural product that binds to cyclophilin but is structurally distinct from cyclosporin A (CsA). We have investigated the cellular and molecular mechanisms of the action of SFA in T lymphocytes. We show that SFA inhibits T cell proliferation induced by IL-2 with an IC(50) of 200 nM. Distinct from CsA, which also binds to cyclophilin, SFA does not affect calcium-dependent IL-2 production, although SFA enhanced IL-2 gene transcription in the same cells. SFA blocks T cell proliferation induced by IL-2 in G(1) with no appreciable effect on IL-2 receptor expression in a manner similar to that of the immunosuppressant rapamycin. Unlike rapamycin, however, SFA has no effect on the phosphorylation or enzymatic activity of p70(s6k) kinase, distinguishing SFA from rapamycin in their mode of action. SFA inhibits hyperphosphorylation of Rb and the activity of cyclin E-cyclin-dependent kinase 2 on IL-2 signaling. These results suggest that SFA has a novel mode of action in comparison with CsA, FK506, and rapamycin, and that its use as a molecular probe may lead to the discovery of a novel target involved in T cell activation.
Zhang
L H
LH
Center for Cancer Research and Departments of Biology and Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Liu
J O
JO
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002460:Cell Line; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D021984:Cyclophilin A / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019169:Jurkat Cells; D007783:Lactones / Q000378:metabolism / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D019927:Cyclin E; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007783:Lactones; D016160:Retinoblastoma Protein; D013141:Spiro Compounds; C121329:sanglifehrin A; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D021984:Cyclophilin A; D020123:Sirolimus