Distinct mechanisms for rescue from apoptosis in Ramos human B cells by signaling through CD40 and interleukin-4 receptor: Role for inhibition of an early response gene, Berg36

The role of interleukin-4 (IL-4) and CD40 signaling in negative regulation of apoptosis in human Ramos B cells induced in response to different agents was investigated. CD40 ligation protected cells from apoptosis induced by calcium ionophore through an initial, rapid and apparently Bcl-2-independent mechanism, associated with up-regulation of Bcl-x(L). However, rescue from apoptosis induced by Inhibition of macromolecular synthesis required several hours of prior stimulation with CD40 ligand/antibody and was accompanied by upregulation of Bcl-2. In contrast, IL-4 did not up-regulate Bcl-2 or Bcl-x(L) and did not inhibit apoptosis induced by inhibitors of macromolecular synthesis. However, IL-4 did protect Ramos cells from apoptosis induced by calcium ionophore and this effect was accompanied by inhibition of ionophore-induced expression of an immediate early gene encoding a 36-kDa zinc-finger protein, Berg36. Anti sense blockade of Berg36 expression partially inhibited ionophore-induced apoptosis to an extent commensurate with the level of IL-4 protection, implicating Berg36 function as a requirement for apoptosis induced through calcium signaling and as a target: for IL-4 through which this cytokine inhibits apoptosis in Ramos B cells, These distinct mechanisms for rescue from apoptosis by CD40 and IL-4 may help explain the co-operative roles of these T cell-derived signals for B cell survival.