Inhibitory Mechanism of Mizoribine on the Antibody Production of Mouse B Cells Stimulated with Lipopolysaccharide
Hiroyuki Kamada (1), Hiromichi Itoh (1), Hiroshi Shibata (1), Takehiro
Koshio (1), Akira Hayashi (2) and Keiji Nakagami (1)
(1) Laboratory for Immunology and (2) Laboratory for Chemistry, Institute for Life Science Research, Asahi Chemical Industry Co., Ltd., 2-1 Samejima, Fuji, Shizuoka 416, Japan
Abstract: It has been reported that the immunosuppressant mizoribine (MZR) inhibits T cell proliferation by depleting intracellular guanine nucleotides via competitive inhibition of inosine 5'-monophosphate (IMP) dehydrogenase in the purine metabolism pathway. This study was performed to determine if the mechanism by which MZR suppresses the proliferation of mouse B cells and antibody production by these cells is dependent on the depletion of intracellular guanine nucleotides. Stimulation of purified splenic B cells of mice with lipopolysaccharide (LPS), a mitogen to B cells, increased both proliferation and antibody production. MZR suppressed both of these functions in a dose-dependent fashion. MZR also caused a decrease in the amount of intracellular guanosine 5'-triphosphate (GTP). When the cultures were grown on plates containing guanosine plus 8-aminoguanosine, the amount of intracellular GTP, which had been reduced by MZR, was restored. Furthermore, the repletion of GTP pools restored both proliferation and antibody production almost to their previous levels. These results suggest that MZR suppresses antibody production and proliferation of B cells by acting directly on B cells. Furthermore, it is suggested that the inhibitory effect of MZR on antibody production, as well as on T cell proliferation, is dependent on the decrease in intracellular guanine nucleotide pools of mouse B cells.
Keywords: Mizoribine, GTP level, B cell, Antibody production