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* Laboratory of Immunopharmacology, Centre d’Etude et de Recherche en Virologie et Immunologie, and
Laboratory of Hematology-Cytogenetic, Hopital E. Herriot, Institut National de la Santé et de la Recherche Médicale, Lyon, France
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 p27Kip1. Therefore, in
activated lymphoblasts, MPA specifically interferes with
cytokine-dependent signals that control cell cycle and blocks activated
T cells in the mid-G1 phase of the cell cycle. Although it
blocks IL-2-mediated proliferation, MPA does not inhibit cell survival
and Bcl-xL up-regulation by IL-2 or other cytokines whose
receptors share the common 
-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.
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