title: Cyclic AMP modulation of human B cell proliferative responses: role of cAMP-dependent protein kinases in enhancing B cell responses to phorbol diesters and ionomycin.
abstract: The ability of cyclic AMP (cAMP) to modulate human B cell proliferative responses and the possible role of cAMP-dependent kinases (PKA) in cAMP modulation of proliferative responses were investigated. The addition of dibutyl cAMP (Bt2 cAMP) or the cAMP-elevating agent forskolin to B cells stimulated by crosslinking surface immunoglobulins (sIg) resulted in a concentration-dependent inhibition of proliferative responses. By contrast, Bt2 cAMP or forskolin enhanced the proliferative responses of B cells after direct stimulation by phorbol myristate acetate (PMA) and the calcium ionophore ionomycin. The inhibition and enhancement of B cell proliferative responses by Bt2 cAMP were observed at different incubation intervals and were not due to temporal shifts of optimal responses. Also, Bt2 cAMP caused only small changes in B cell RNA synthesis compared to modulation of proliferative responses. Exposure of B cells to Bt2 cAMP rapidly activated PKA. Blocking Bt2 cAMP activation of PKA with the kinase inhibitor HA1004 prevented Bt2 cAMP enhancement of B cell responses after direct stimulation by PMA and ionomycin. In reciprocal experiments, the kinase inhibitor H7 resulted in some inhibition of PKC activation but did not inhibit Bt2 cAMP activation of PKA or Bt2 cAMP enhancement of proliferative responses. Other experiments demonstrated that B cells treated with Bt2 cAMP had selective increases in the de novo phosphorylations of two endogenous substrates which reflected PKA activation. Furthermore, concentrations of HA1004 or H8 which inhibited Bt2 cAMP enhancement of proliferative responses also inhibited PKA phosphorylations of these substrates whereas H7 did not. Thus, elevations of cAMP can enhance or inhibit human B cell proliferative responses to different stimuli and the activation of PKA is important for cAMP enhancement of certain responses.
authors.affiliation: William H. Davis Medical Research Center, Ohio State University, Columbus 43210.
authors.forename: R L
authors.initials: RL
authors.lastname: Whisler
authors.forename: L
authors.initials: L
authors.lastname: Beiqing
authors.forename: I S
authors.initials: IS
authors.lastname: Grants
authors.forename: Y G
authors.initials: YG
authors.lastname: Newhouse
mesh_terms: D000595:Amino Acid Sequence; D000888:Antibodies, Anti-Idiotypic; D001402:B-Lymphocytes / Q000187:drug effects*; D003994:Bucladesine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008969:Molecular Sequence Data; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000187:drug effects*; D013449:Sulfonamides
chemical_list: D000888:Antibodies, Anti-Idiotypic; D007546:Isoquinolines; D010703:Phorbol Esters; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D015759:Ionomycin; D003994:Bucladesine; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D011494:Protein Kinases