Two inhibitors of DNA-synthesis lead to inhibition of cytokine production via a different mechanism.
Methotrexate (MTX) and mycophenolic acid (MPA) are used in the clinic for their immunosuppressive properties. MTX is widely used for the treatment of rheumatoid arthritis (RA). MPA is used to prevent graft rejection and is now experimentally used in systemic lupus erythematosis and RA. It is known that both drugs interfere with DNA synthesis. However, the precise mechanism of action is still debated. We have analysed the effect of the drugs on cytokine production in whole blood during short cultures. The production of T-cell cytokines was inhibited by both drugs. MTX inhibits cytokine production because MTX induces apoptosis in activated T-cells. MPA inhibits cytokine production by preventing T-cells to progress to the S-phase of the cell cycle. Cytokine production by monocytes was slightly decreased by the drugs. The reason for this inhibition is not clear. These results indicate that T-cells are the main target cells of the immunosuppressive drugs MPA and MTX.
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Sanquin Research at CLB, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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D000818:Animals; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis* / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects; D008727:Methotrexate / Q000494:pharmacology; D009173:Mycophenolic Acid / Q000378:metabolism / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D019384:Nucleic Acid Synthesis Inhibitors; D019271:Hypoxanthine; D004247:DNA; D009173:Mycophenolic Acid; D008727:Methotrexate