Mycophenolic acid inhibits IL-2-dependent T cell proliferation, but not IL-2-dependent survival and sensitization to apoptosis.
Mycophenolic acid (MPA), the active metabolite of the immunosuppressive drug mycophenolate mofetil, is a selective inhibitor of inosine 5'-monophosphate dehydrogenase type II, a de novo purine nucleotide synthesis enzyme expressed in T and B lymphocytes and up-regulated upon cell activation. In this study, we report that the blockade of guanosine nucleotide synthesis by MPA inhibits mitogen-induced proliferation of PBL, an effect fully reversed by addition of guanosine and shared with mizoribine, another inhibitor of inosine 5'-monophosphate dehydrogenase. Because MPA does not inhibit early TCR-mediated activation events, such as CD25 expression and IL-2 synthesis, we investigated how it interferes with cytokine-dependent proliferation and survival. In activated lymphoblasts that are dependent on IL-2 or IL-15 for their proliferation, MPA does not impair signaling events such as of the extracellular signal-regulated kinase 2 and Stat5 phosphorylation, but inhibits down-regulation of the cyclin-dependent kinase inhibitor p27(Kip1). Therefore, in activated lymphoblasts, MPA specifically interferes with cytokine-dependent signals that control cell cycle and blocks activated T cells in the mid-G(1) phase of the cell cycle. Although it blocks IL-2-mediated proliferation, MPA does not inhibit cell survival and Bcl-x(L) up-regulation by IL-2 or other cytokines whose receptors share the common gamma-chain (CD132). Finally, MPA does not interfere with IL-2-dependent acquisition of susceptibility to CD95-mediated apoptosis and degradation of cellular FLIP. Therefore, MPA has unique functional properties not shared by other immunosuppressive drugs interfering with IL-2R signaling events such as rapamycin and CD25 mAbs.
Quéméneur
Laurence
L
Laboratory of Immunopharmacology, Centre d'Etude et de Recherche en Virologie et Immunologie, Institut National de la Santé et de la Recherche Médicale, Lyon, France.
Flacher
Monique
M
Gerland
Luc-Marie
LM
Ffrench
Martine
M
Revillard
Jean-Pierre
JP
Bonnefoy-Berard
Nathalie
N
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007114:Immunization; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019409:Interleukin-15 / Q000037:antagonists & inhibitors / Q000502:physiology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D009173:Mycophenolic Acid / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology
D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D019409:Interleukin-15; D007376:Interleukin-2; D019014:fas Receptor; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D020123:Sirolimus