Jatrophone and 12- O-tetradecanoyl phorbol-13-acetate antagonism of stimulation of natural killer activity and lymphocyte proliferation

• Published in: European journal of pharmacology 1996-10, Vol.312 (3), p.333-339
• Main Authors: de Moraes, Vera Lucia Gonçalves, Rumjanek, Vivian M., Calixto, João B.
• Format: Article
• Language: English
• Subjects: 12- O-Tetradecanoylphorbol 13-acetate; Animals; Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - metabolism; Biological and medical sciences; Calcium - metabolism; CD69; Cell Division - drug effects; Diterpenes - pharmacology; General pharmacology; Humans; Interleukin-2; Jatrophone; Killer Cells, Natural - drug effects; Lectins, C-Type; Lymphocyte proliferation; Lymphocytes - cytology; Lymphocytes - drug effects; Lymphocytes - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; Natural killer activity; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Phytohemagglutinins - pharmacology; Protein kinase C; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(96)00488-8

We have recently reported that the diterpene jatrophone antagonizes the effects of phorbol ester in pharmacogical studies. In order to investigate further whether this action is associated with an inhibition of protein kinase C activity, we examined the effect of jatrophone on the stimulation of lymphocyte activities which are dependent on the protein kinase C pathway. Jatrophone (0.02–0.32 μM) caused concentration-dependent and equipotent inhibition of human lymphocyte proliferation induced by 5 μg/ml of phytohemagglutinin or by a combination of 100 ng/ml of 12- O-tetradecanoyl phorbol-13-acetate (TPA) plus 0.15 μM ionomicyn, with IC 50 values (and their 95% confidence limits) of 53.4 (42.6–65.3) nM and 48.4 (39.4–59.8) nM, respectively. Jatrophone also blocked, in a concentration-dependent fashion, the murine lymphocyte proliferation stimulated by 5 μg/ml of concanavalin A, with an IC 50 value of 63.5 (51.2–76.5) nM. The inhibition was not due to a toxic effect as the pre-incubation of lymphocytes for 48 h with 0.32 μM jatrophone did not impair the proliferation after removal of the diterpene from the culture medium. Human lymphocytes when pre-treated with 10 ng/ml TPA had a 3 times higher spontaneous natural killer activity against K 562 cells and an increased expression of CD69. In addition, jatrophone inhibited both spontaneous and TPA-stimulated natural killer activity and the expression of CD69. Jatrophone concentrations that inhibited 75% of lymphocyte proliferation did not impair the intracellular increase in Ca 2+ flux in lymphocytes stimulated by phytohemagglutinin. These results indicate that jatrophone is a potent inhibitor of activation of lymphocytes, probably through inhibition of the protein kinase C pathway.