REGULATION OF BCL-2, BCL-X(L) AND BAX IN THE CONTROL OF APOPTOSIS BY HEMATOPOIETIC CYTOKINES AND DEXAMETHASONE

Treatment of M1 myeloid leukemic cells with interleukin 6 (IL-6) or de xamethasone (DEX), both of which induce differentiation in these cells , down-regulated expression of the apoptosis-suppressing gene bcl-2 an d the apoptosis-promoting gene bax but up-regulated expression of the apoptosis-suppressing gene bcl-X(L). There was a higher expression of bcl-X(L) in cells treated with DEX or DEX plus IL-6 compared to cells treated with IL-6 alone. The alternatively spliced bcl-X gene, bcl-X(s ), which interferes with the action of bcl-2, was not expressed. Treat ment with IL-6 increased the susceptibility of these cells to inductio n of apoptosis by Adriamycin or cycloheximide, but treatment with DEX or with IL-6 and DEX did not. Withdrawal of DEX after up-regulation of bcl-X(L) resulted in a decrease in bcl-X(L) expression and a concomit ant increase in cell susceptibility to induction of apoptosis. Another myeloid leukemia that shows barely detectable expression of bcl-2 als o showed up-regulated expression of bcl-X(L) but no change in bax afte r induction of differentiation with granulocyte-macrophage colony-stim ulating factor, and this reduced cell susceptibility to induction of a poptosis by Adriamycin or cycloheximide. The results indicate that the related apoptosis-regulating genes bcl-2, bcl-X(L), and bax are diffe rently regulated and that up-regulation of bcl-X(L) expression may com pensate for downregulation of bcl-2 in the balance between genes that control apoptosis.