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...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2002-09, Vol.169 (5), p.2747-2755
Main Authors: Quemeneur, Laurence, Flacher, Monique, Gerland, Luc-Marie, Ffrench, Martine, Revillard, Jean-Pierre, Bonnefoy-Berard, Nathalie
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Apoptosis - immunology
Cell Division - drug effects
Cell Division - immunology
Cell Survival - drug effects
Cell Survival - immunology
Cells, Cultured
Enzyme Inhibitors - pharmacology
fas Receptor - physiology
Growth Inhibitors - pharmacology
Humans
Immunization
Immunosuppressive Agents - pharmacology
IMP Dehydrogenase - antagonists & inhibitors
IMP Dehydrogenase - biosynthesis
Interleukin-15 - antagonists & inhibitors
Interleukin-15 - physiology
Interleukin-2 - antagonists & inhibitors
Interleukin-2 - physiology
Lymphocyte Activation - drug effects
Mycophenolic Acid - pharmacology
Signal Transduction - drug effects
Signal Transduction - immunology
Sirolimus - pharmacology
T-Lymphocytes - cytology
T-Lymphocytes - drug effects
T-Lymphocytes - enzymology
T-Lymphocytes - immunology
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.169.5.2747