Type I and type II cyclic AMP-dependent protein kinase as opposite effectors of lymphocyte mitogenesis

Abstract

THE role of cyclic AMP in the regulation of cell growth and differentiation has been extensively investigated in many cell types following various growth stimuli1,2. In recent years, peripheral blood lymphocytes treated with antigens3, plant lectins4, lipopolysaccharides5, or periodate oxidation6 have served as a model system for assessing whether cyclic AMP is involved in the regulation of the mitogenic response promoted in these cells by the above classes of agents7,8. There are two conflicting hypotheses, as outlined by Friedman1, concerning the role of cyclic AMP in lymphocyte proliferation. The first hypothesis suggests that the increase in cyclic AMP levels following mitogen stimulation8 and the subsequent increase in 32P incorporated into F1 histones9 and certain cystosol proteins10 implicates cyclic AMP as a positive mediator of mitogenesis in lymphocytes. The other hypothesis reasons that cyclic AMP inhibits proliferation, and this hypothesis is supported primarily by observations from several laboratories that raising the intracellular cyclic AMP level through the use of phosphodiesterase inhibitors11, prostaglandins12, or cyclic AMP analogues11,13–15 effectively inhibits mitogen-stimulated RNA and DNA synthesis. We present here evidence that may help resolve this apparent paradox. Incubation of Ficoll–Hypaque purified human peripheral blood lymphocytes with concanavalin A (conA) leads to the activation of only type I cyclic AMP-dependent protein kinase in these cells even though there are significant amounts of both type I and type II kinase present. But, the addition of dibutyryl cyclic AMP (DBcAMP) to the conA-stimulated lymphocytes at a concentration sufficient to block the synthesis of RNA and DNA results in the activation of both type I and type II cyclic AMP-dependent protein kinase. It therefore seems likely that while the activation of type I protein kinase represents a positive component in the progression of events promoted in a lymphocyte by a mitogenic signal (as it does in other cell types in which a trophic response is evoked), the activation of type II protein kinase (or perhaps types I and II in concert) represents a mechanism by which a negative influence can be imposed on the proliferative process by the generation of abnormally high levels of intracellular cyclic AMP.