Mycophenolic acid increases apoptosis, lysosomes and lipid droplets in human lymphoid and monocytic cell lines

Background. Mycophenolic acid (MPA), a selective inhibitor of inosine monop hosphate dehydrogenase, is the active agent of the immunosuppressive drug, mycophenolate mofetil (MMF). Previous studies have shown that MPA inhibits DNA synthesis in T and B lymphocytes by blocking de novo guanosine synthesi s, and that MPA induces monocyte differentiation. MMF is being used for pre vention of organ graft rejection and has also shown efficacy in rheumatoid arthritis trials. This study was designed to determine if apoptosis also pl ays a role in the immunosuppressive and anti-inflammatory effects of MMF. Methods, Cultured human T lymphocytic (MOLT-4) and monocytic (THP-1 and U93 7) cell lines were treated with MPA, Apoptosis, cell viability, DNA content , lipid content, cell volume, and lysosomes were measured by a variety of m icroscopic, flow cytometric, and biochemical techniques, Results, MPA inhibits proliferation, arrests cell cycle in S phase, and inc reases apoptosis in all three cell lines. Exogenous guanosine added within 24 hr of MPA treatment, but not later, partially reversed MPA-induced apopt osis in MOLT-4 cells. MPA increased lipid droplets in all three cell lines and increased both cell volumes and numbers of lysosomes in the monocytic c ell lines. In both monocytic cell lines, MPA also reduced the number of nuc lei containing nucleoli and greatly increased neutral lipids, primarily tri acylglycerols, suggesting that these cells were differentiating. Conclusions. Increased apoptosis and terminal differentiation of both lymph ocytes and monocytes may promote the antiproliferative, immunosuppressive, and anti-inflammatory effects of MMF seen clinically in transplantation and rheumatoid arthritis.