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