Differential Regulatory Effects of cAMP-Elevating Agents on Human Normal and Neoplastic B Cell Functional Response Following Ligation of Surface Immunoglobulin and CD40

The B cell response to ligation of surface immunoglobulin (sIg) and CD40 is dependent on the stage of cellular differentiation of the population studied. Cross-linking sIg promotes proliferation of follicular mantle (FM) B cells, rescues germinal center (GC) B cells from spontaneous apoptosis but induces apoptosis in susceptible Burkitt lymphoma (BL) B cells; signals transduced through CD40 induce resting FM B cells to enter cell cycle while promoting GC and BL B cell survival. This study investigates whether the 3′, 5′-cyclic adenosine monophosphate (cAMP)-dependent second-messenger pathway plays a role in the regulation of these sIg- and CD40-promoted B cell responses, using prostaglandin E2(PGE2) and forskolin to artificially increase intracellular levels of cAMP. The Epstein–Barr virus (EBV)-genome-negative BL B cell line Ramos is susceptible to growth arrest and apoptosis triggered by calcium ionophore, anti-IgM and forskolin but not by PGE2; forskolin does not affect the outcome of anti-IgM treatment. Anti-CD40 rescues Ramos-BL B cells from ionophore- and anti-IgM-triggered but not forskolin-triggered growth arrest and apoptosis; moreover, forskolin and anti-CD40 act additively and independently for enhanced growth inhibition. By contrast, both forskolin and PGE2potentiate the proliferative response of FM B cells cultured with anti-Ig and anti-CD40 together but not individually. Forskolin and PGE2fail to affect the spontaneous apoptosis and anti-Ig- and anti-CD40-promoted survival of GC B cells. Thus, the cAMP-dependent second messenger pathway can differentially influence the BL, FM, and GC B cell functional response to signals transduced through sIg and CD40.