Inhibition of human B cell activation by diterpine forskolin: interference with B cell growth factor-induced G1 to S transition of the B cell cycle.
We have previously demonstrated that a series of sequential steps are involved in the induction of a resting human B cell to proliferate. In this system, initial activation signals were delivered by either in vivo or in vitro stimulation, and proliferative signals were delivered by a B cell growth factor (BCGF) that was derived from a human T-T cell hybridoma. The involvement of adenosine 3',5'-monophosphate (cAMP) in regulating the growth and differentiation of lymphocytes has been of considerable interest. Diterpine forskolin has been reported to be a unique adenylate cyclase activator in membranes from mammalian tissues that results in elevations of intracytoplasmic cAMP. We have examined the effect of this drug on the progression of human B cells through their activation cycle. It was found that forskolin causes a rapid and sustained increase of cytoplasmic cAMP in purified small and large B cells. In the in vitro costimulation of small resting B cells with anti-mu plus BCGF, forskolin inhibited the proliferative response of B cells in a dose-dependent manner. This forskolin-mediated suppression of B cell proliferation was found when the drug was added to the cultures as late as 36 hr after initial stimulation. Of note is the fact that the anti-mu-induced RNA synthesis as well as cell enlargement in resting B cells was not inhibited by the addition of forskolin, whereas BCGF-induced proliferative response of activated B cells was markedly inhibited by the drug. Thus, these data demonstrate that forskolin, an agent that elevates cytoplasmic cAMP levels, has relatively little effect on early events in the human B cell cycle (G0 to G1) transition, but selectively inhibits the progression of BCGF-induced G1 to S phase transition of B cells.
D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002648:Child; D005576:Colforsin; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004224:Diterpenes / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D015847:Interleukin-4; D007399:Interphase / Q000187:drug effects*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D008222:Lymphokines / Q000494:pharmacology
D004224:Diterpenes; D006131:Growth Inhibitors; D006133:Growth Substances; D008222:Lymphokines; D005576:Colforsin; D015847:Interleukin-4; D004247:DNA; D000242:Cyclic AMP