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Cyclic AMP counteracts mitogen‐induced inositol phosphate generation and increases in intracellular Ca 2+ concentrations in human lymphocytes
Author(s) -
Tits Lambertus J.H.,
Michel Martin C.,
Motulsky Harvey J.,
Maisel Alan S.,
Brodde OttoErich
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb09782.x
Subject(s) - forskolin , isoprenaline , intracellular , inositol phosphate , phosphodiesterase inhibitor , medicine , endocrinology , inositol , phosphodiesterase 3 , ionomycin , phosphodiesterase , extracellular , chemistry , ibmx , cholera toxin , protein kinase a , biology , biochemistry , kinase , stimulation , enzyme , receptor
1 The effects of increases in intracellular adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) on mitogen‐induced generation of inositol phosphates and increases in intracellular Ca 2+ concentration were investigated in human peripheral blood mononuclear leukocytes (MNL). 2 The mitogens concanavalin A (Con A), pokeweed mitogen (PWM) and phytohaemagglutinin (PHA) concentration‐dependently stimulated generation of inositol phosphates. Catecholamines inhibited this process with an order of potency: isoprenaline > adrenaline > noradrenaline indicating involvement of β 2 ‐adrenoceptors. This order of potency was also consistent with the catecholamine potencies for stimulating the generation of cyclic AMP. 3 In addition to catecholamines, the cyclic AMP formation‐stimulating agents prostaglandin E 1 (PGE 1 ) and forskolin concentration‐dependently inhibited mitogen‐induced inositol phosphate generation, too. Moreover, the inhibitory effect of isoprenaline was potentiated by co‐incubation with the phosphodiesterase inhibitor isobutylmethylxanthine demonstrating that these inhibitory effects were mediated by cyclic AMP. 4 Con A and PHA concentration‐dependently increased the intracellular Ca 2+ concentration in human MNL (assessed by the fluorescent indicator dye Fura‐2). This increase was almost completely blocked by chelation of extracellular Ca 2+ , demonstrating influx rather than mobilization from intracellular stores. 5 The elevation of intracellular Ca 2+ was not blocked by pretreatment with pertussis toxin, 100 ng ml −1 , for 16 h. 6 Isoprenaline, PGE 1 , and forskolin, however, inhibited the mitogen‐stimulated elevation of intracellular Ca 2+ . This inhibition was enhanced by the phosphodiesterase inhibitors isobutylmethylxanthine and Ro 20–1724, demonstrating mediation by cyclic AMP. 7 We conclude that catecholamines and other cyclic AMP increasing agents can inhibit mitogen‐stimulated generation of inositol phosphates and elevation of intracellular Ca 2+ in resting human MNL. Since generation of inositol phosphates and increases in intracellular Ca 2+ are very early events in activation of MNL, attenuation of these events might well contribute to the inhibitory effect of cyclic AMP on MNL function.