Specific dual effect of cycloheximide on B lymphocyte apoptosis: Involvement of CPP32/caspase-3

Cycloheximide (CHX) is known to stimulate or to prevent apoptosis, accordin g to the cell type used. We found that CHX, in a dose-dependent way, exerte d the two opposite effects in B lymphocytes. CHXhigh (2.5 mu g/mL) inhibite d protein synthesis (>90%) and greatly increased B cell apoptosis but faile d to prevent apoptosis induction by dexamethasone (DEX) or dibutyryl-cAMP ( dbcAMP), which is in opposition with CHX activity in thymocytes. On the con trary, CHXlow (0.05 mu g/mL), modestly inhibited protein synthesis (<15%) a nd reduced spontaneous as well as drug-induced apoptosis and further augmen ted the protection conferred by interleukin-4 or lipopolysaccharide. To exa mine the role of caspases in CHX effects, we used the broad spectrum peptid e caspase inhibitor Z-VAD-fmk: it totally abrogated spontaneous as well as drug- and CHXhigh-induced cell death. Apoptosis was associated with CPP32/c aspase-3 activation, since cleavage of CPP32/caspase-3 and caspase-3 activi ty were increased by DEX, dbcAMP as well as by CHXhigh treatment. Meanwhile , caspase-3 activity was reduced by CHXlow treatment. Therefore, CHX exerts opposite effects on B lymphocyte apoptosis which are associated with a dua l action on caspase-3 activation. BIOCHEM PHARMACOL 58;1:85-93, 1999. (C) 1 999 Elsevier Science Inc.