Mycophenolic acid inhibits inosine 5'-monophosphate dehydrogenase and suppresses production of pro-inflammatory cytokines, nitric oxide, and LDH in macrophages.
Mycophenolic acid (MPA) inhibits reversibly inosine 5(')-monophosphate dehydrogenase, an enzyme involved in the de novo synthesis of guanine nucleotides. Previously, mycophenolate mofetil (MMF), the pro-drug of MPA, was shown to exert beneficial effects on the systemic lupus erythematosus (SLE)-like disease in MRLlpr/lpr mice. In this study MPA's immunomodulating effects in vitro on the murine macrophage cell line IC-21 were investigated. The cells were exposed to MPA together with lipopolysaccharide and IFN-gamma. Cytokine, NO(2)(-), and lactate dehydrogenase levels in supernatants and cell lysates were analysed as well as the proliferation of IC-21 cells. MPA exposure reduced the total levels of all molecules investigated and suppressed the proliferation. All MPA-induced effects were reversed by the addition of guanosine to the cultures. Since macrophages play a role in lupus nephritis, our results indicate that modulation of macrophages may be involved in the ameliorating effects of MMF in SLE.
Jonsson
Charlotte A
CA
Department of Rheumatology and Inflammation Research, Göteborg University, Guldhedsgatan 10A, S-413 46 Göteborg, Sweden. charlotte.jonsson@rheuma.gu.se
Carlsten
Hans
H
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D003470:Culture Media; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006151:Guanosine; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007375:Interleukin-1 / Q000096:biosynthesis*; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D051379:Mice; D009173:Mycophenolic Acid / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D003470:Culture Media; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D006151:Guanosine; D009569:Nitric Oxide; D007168:IMP Dehydrogenase; D007770:L-Lactate Dehydrogenase; D009173:Mycophenolic Acid