title: Mycophenolic acid and methotrexate inhibit lymphocyte cytokine production via different mechanisms.
abstract: Mycophenolic acid (MPA) and methotrexate (MTX) are immunosuppressive drugs used for the treatment of various immunological disorders. MPA is an inhibitor of inosine monophosphate dehydrogenase and MTX is a folate antagonist that inhibits tetrahydrofolate reductase. Production of T cell cytokines in whole blood cultures, as well as in PBMC cultures, is inhibited by a low concentration of both drugs. Inhibition of cytokine production after monocyte stimulation was less evident. The mechanism by which inhibition is achieved is different for both drugs. Inhibition of T cell cytokine production by MPA was more profound and started earlier compared to the inhibition by MTX. MTX induced apoptosis in T cells that became activated, whereas MPA prevented activation of T cells by arresting the cell cycle in the G0/G1 phase. Addition of guanosine and adenosine can overcome this cell cycle arrest, even after several days. Furthermore MPA inhibited the expression of activation markers HLA-DR and CD71 on T cells. The observation that MTX cannot prevent T cell activation but induces apoptosis in activated T cells, and that MPA reversibly prevents activation of T cells could explain the immunosuppressive effects of both these drugs.
authors.affiliation: Dept. of Immunopathology, CLB and Laboratory for Experimental Clinical Immunology, Academic Medical Center, University of Amsterdam, The Netherlands. s_de_lathouder@clb.nl
authors.forename: Sacha
authors.initials: S
authors.lastname: de Lathouder
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Gerards
authors.forename: Els R
authors.initials: ER
authors.lastname: de Groot
authors.forename: Marijke
authors.initials: M
authors.lastname: Valkhof
authors.forename: Lucien A
authors.initials: LA
authors.lastname: Aarden
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008727:Methotrexate / Q000494:pharmacology*; D009173:Mycophenolic Acid / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D009173:Mycophenolic Acid; D008727:Methotrexate