title: Potentiation of lymphokine-activated killer cell differentiation and lymphocyte proliferation by stimulation of protein kinase C or inhibition of adenylate cyclase.
abstract: Interleukin 2 (IL-2) stimulated the differentiation of human peripheral blood leukocytes into lymphokine-activated killer cells, as well as DNA synthesis of human T lymphocytes. Both effects of IL-2 could be inhibited by prostaglandin E2, a potent stimulator of adenylate cyclase; however, the inhibitory effect of prostaglandin E2 could be overcome by increased concentrations of IL-2. The opposite effects of IL-2 and prostaglandin E2 were paralleled by their respective abilities to inhibit and stimulate cAMP production in intact cells. Other agents, which inhibit adenylate cyclase directly (somatostatin, beta-endorphin, UK 14.3041) or indirectly by activation of protein kinase C (phenylephrine), could stimulate both differentiation and proliferation. None of these agents alone or in combination were as effective as maximal concentrations of IL-2. However, all agents potentiated differentiation and proliferation induced by submaximal and maximal concentrations of IL-2. Additionally, combinations of agents which stimulated protein kinase C with those that inhibited adenylate cyclase were additive in the potentiation of IL-2-induced differentiation. Neither inhibition nor potentiation of IL-2-induced lymphokine-activated killer cell differentiation was accompanied by changes in Tac expression or gamma-interferon production. The data indicate that the stimulation of lymphokine-activated killer cell differentiation and lymphocyte proliferation in human cells share a common initial biochemical signal. Although the inhibition of adenylate cyclase is not sufficient to maximally stimulate either process and cannot bypass the requirement for IL-2, modulation of this enzyme complex, positively or negatively, can regulate the ultimate physiologic response to IL-2.
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000954:Antigens, Surface / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D015232:Dinoprostone; D019204:GTP-Binding Proteins / Q000378:metabolism; D007372:Interferons / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D010656:Phenylephrine / Q000494:pharmacology; D011458:Prostaglandins E / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D013004:Somatostatin / Q000494:pharmacology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000316:Adrenergic alpha-Agonists; D000954:Antigens, Surface; D007376:Interleukin-2; D011458:Prostaglandins E; D010656:Phenylephrine; D013004:Somatostatin; D007372:Interferons; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D015232:Dinoprostone; D007545:Isoproterenol