Mizoribine has been shown to have beneficial effects in the treatment of rh
eumatoid arthritis and lupus nephritis, in which abnormal B cell functions
are involved. Previous studies demonstrated that mizoribine directly suppre
sses the function of human B cells. The current study explored in derail th
e mechanism of the suppression of human B cell responses by mizoribine at t
he molecular level. Highly purified peripheral blood B cells obtained from
normal healthy individuals were stimulated with Staphylococcus aureus Cowan
I (SAC) plus IL-2 in the presence or absence of mizoribine or methotrexate
for 48 h to 72 h. The expression of cyclin A mRNA was determined by semiqu
antitative reverse transcriptase-polymerase chain reaction followed by Sout
hern hybridization. Although at pharmacologically attainable concentrations
both mizoribine and methotrexate suppressed the production of IgM of SAG-a
ctivated B cells, mizoribine, but not methotrexate, decreased the expressio
n of cyclin a protein as well as mRNA in B cells stimulated with SAC + IL-2
. Of note, mizoribine facilitated the degradation of cyclin A mRNA in the p
resence of actinomycin D, indicating that mizoribine shortens the stability
of cyclin A mRNA. The results indicate that mizoribine suppresses the expr
ession of cyclin A mRNA in human B cells by down-regulating its stability,
and thus down-regulates their responses.