Synergistic action of calcium ionophore A23187 and protein kinase C activator bryostatin 1 on human B cell activation and proliferation.
In this study we have examined the immunostimulatory effects of the macrocyclic lactone bryostatin 1 on various aspects of B cell activation and proliferation using human tonsillar B cells. Bryostatin 1 is an activator of protein kinase C (PKC) and its properties were compared to those of the classical PKC activator phorbol 12-myristate 13-acetate (PMA), a phorbol ester. Time-course kinetics and dose-response curves of RNA and DNA synthesis induced by bryostatin 1 or PMA were comparable, albeit the phorbol ester was significantly more potent. The responses triggered by both bryostatin 1 and PMA could be blocked by the PKC inhibitor H7. Bryostatin 1 and PMA mediated similar effects with regard to the activation parameters, increase in cell size, expression of activation-associated antigens and hyperexpression of major histocompatibility complex class II antigens. Addition of the calcium ionophore A23187 to bryostatin 1-treated cultures resulted in synergistically enhanced activation and proliferation responses, and this potentiation by A23187 could be inhibited by cyclosporin A. Bryostatin 1 antagonized the effects of PMA-triggered stimulation in a time- and dose-dependent manner. The basis for this modulation of PMA-induced effects and the reason for the difference in the abilities of the two agents to stimulate B cells is unclear; possibly, bryostatin 1 and PMA activate different isoforms of PKC and elicit different signals on intracellular biochemical pathways. Bryostatin 1 lacks the tumor-promoting activity of PMA and is a potent anti-neoplastic substance. These features together with its immunomodulatory properties qualify bryostatin 1 as a candidate for in vivo use as a biological response modifier.
Drexler
H G
HG
Department of Hematology, Royal Free Hospital School of Medicine, London.
Gignac
S M
SM
Pettit
G R
GR
Hoffbrand
A V
AV
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000917:Antibody Formation / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D054713:Bryostatins; D000001:Calcimycin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D018942:Macrolides; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D054713:Bryostatins; D003524:Cyclosporins; D007546:Isoquinolines; D007783:Lactones; D018942:Macrolides; D010879:Piperazines; D000001:Calcimycin; C046785:bryostatin 1; D012313:RNA; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D004247:DNA; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate