title: Differential regulatory effects of cAMP-elevating agents on human normal and neoplastic B cell functional response following ligation of surface immunoglobulin and CD40.
abstract: 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 PGE2 potentiate the proliferative response of FM B cells cultured with anti-Ig and anti-CD40 together but not individually. Forskolin and PGE2 fail 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.
authors.affiliation: School of Biological and Molecular Sciences, Oxford Brookes University, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Kelly
authors.forename: K A
authors.initials: KA
authors.lastname: Knox
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D002051:Burkitt Lymphoma / Q000276:immunology; D019013:CD40 Antigens / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002461:Cell Line, Transformed; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis*; D015232:Dinoprostone / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology; D004854:Herpesvirus 4, Human; D006801:Humans; D007072:Immunoglobulin D / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D015759:Ionomycin / Q000494:pharmacology; D014066:Palatine Tonsil / Q000166:cytology; D011947:Receptors, Antigen, B-Cell / Q000187:drug effects* / Q000276:immunology; D015290:Second Messenger Systems / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D006131:Growth Inhibitors; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; C039951:anti-IgD; C044203:anti-IgM; D005576:Colforsin; D015759:Ionomycin; D000242:Cyclic AMP; D015232:Dinoprostone