INHIBITION BY GLUCOCORTICOID AND STAUROSPORINE OF IL-4-DEPENDENT CD23PRODUCTION IN B-LYMPHOCYTES IS REVERSED ON ENGAGING CD40

IL-4 synergizes with signals delivered through CD40 both for the induc tion of CD23/FcepsilonRII expression and for IgE synthesis. Moreover, engagement of CD40 on the B cell surface by MoAb overcomes the ability of interferons, transforming growth factor-beta, or anti-CD 19 to inh ibit IL-4-dependent change. We now report that occupancy of CD40 relie ves potent suppression of IL-4-induced CD23 production by glucocortico id or the relatively broad-acting kinase inhibitor staurosporine. Inte rruption of the IL-4 signal was observed with concentrations of stauro sporine considered to be selective for protein kinase C (PKC) inhibiti on (IC50 = 10 nM) but not with genistein or tyrphostins, effective inh ibitors of tyrosine kinase activity. On ligation of CD40, staurosporin e no longer inhibited the IL-4 signal: at concentrations of between 1 and 20 nm, staurosporine actually increased by as much as 100% the rat e of CD23 production stimulated on simultaneous activation through CD4 0 and IL-4R. Such augmentation was not observed when the more specific PKC inhibitor RO-31-8220 was used; indeed, CD40 engagement was unable to overcome the ability of this inhibitor to block IL-4-promoted CD23 induction (IC50 = 10 mum). Occupancy of CD40 did, however, thwart com pletely the usual ability of prednisolone to inhibit the IL-4 signal l eading to CD23 induction. Activation through CD40 left inhibition of p horbol ester-induced CD23 expression by staurosporine, RO-31-8220, or glucocorticoid unchecked. These findings further highlight the intimat e level of cross-talk existing between CD40 and IL-4R on resting B lym phocytes to promote CD23 expression, a phenotypic change which prelude s IgE synthesis.