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Background. Mycophenolic acid (MPA), a selective inhibitor of inosine monophosphate 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 synthesis, and that MPA induces monocyte differentiation. MMF is being used for prevention of organ graft rejection and has also shown efficacy in rheumatoid arthritis trials. This study was designed to determine if apoptosis also plays a role in the immunosuppressive and anti-inflammatory effects of MMF. Methods. Cultured human T lymphocytic (MOLT-4) and monocytic (THP-1 and U937) cell lines were treated with MPA. Apoptosis, cell viability, DNA content, lipid content, cell volume, and lysosomes were measured by a variety of microscopic, flow cytometric, and biochemical techniques. Results. MPA inhibits proliferation, arrests cell cycle in S phase, and increases apoptosis in all three cell lines. Exogenous guanosine added within 24 hr of MPA treatment, but not later, partially reversed MPA-induced apoptosis 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 cell lines. In both monocytic cell lines, MPA also reduced the number of nuclei containing nucleoli and greatly increased neutral lipids, primarily triacylglycerols, suggesting that these cells were differentiating. Conclusions. Increased apoptosis and terminal differentiation of both lymphocytes and monocytes may promote the antiproliferative, immunosuppressive, and anti-inflammatory effects of MMF seen clinically in transplantation and rheumatoid arthritis.

Enprostil, a synthetic analogue of prostaglandin E2, is known to be a potent inhibitor of gastric acid secretion, and has marked anti-ulcer activity in rodents. Enprostil was administered in doses ranging from 15 to 250 micrograms/kg to rats prepared using the Shay procedure. Three hours later, the rats' stomachs were removed and processed either for the chemical determination of mucus, or for scanning electron microscopy. For the chemical determination, the secreted gastric juice was removed and the adherent gastric mucus was eluted with 2 M sodium chloride. The anthrone method was used to determine the mucus present. Enprostil was found to significantly increase gastric mucus at a dose of 60 micrograms/kg when measured by the anthrone test. Enprostil administered by the oral route was most effective in stimulating mucus secretion, suggesting a local or topical action of enprostil on mucus-secreting cells. Scanning electron microscopy of rat fundic mucosa after enprostil administration (50 to 100 micrograms/kg) revealed the presence of thin veil-like layers covering the epithelial surface, which was interpreted as an increase in mucus secretion. Higher magnifications (X 2,000) clearly showed the layers of mucus covering the surface epithelial cells. Enprostil's apparent increase of gastric mucus secretion may contribute to its anti-ulcer activity and may promote gastric healing.