Altered beta-adrenoceptor function associated to protein kinase C activation in hyperproliferative T lymphocytes.

beta-Adrenoceptor (betaAR) expression and function as well as its modulation via intracellular transduction signals, were analyzed on the T cell lymphoma BW5147. Independently to the kinetic of proliferation and relative to the number of receptors displayed in normal T lymphocytes, BW5147 cells displayed a decreased number of betaAR, uncoupled to adenylate cyclase, but coupled to protein kinase C stimulation. This last effect was impaired by a beta-antagonist and by blockers of the enzymatic pathways involved in T lymphocyte proliferation, inducing a recovery of betaAR sites. Down-regulation of betaAR would implicate the loss of a negative neuroimmune control mechanism for lymphocyte proliferation. The coupling of the remaining sites to a positive signal for cellular activation, would contribute to establish an hyperproliferative state.

Down-regulation of beta-adrenergic receptors induced by mitogen activation of intracellular signaling events in lymphocytes.

The expression of beta-adrenergic receptors on murine lymphocytes stimulated with concanavalin A was studied. A decrease in beta-adrenoceptor number on T lymphocytes and a diminished response to specific agonist stimulation at the peak of proliferation was found. The blockade of cell proliferation by tyrosine kinases or protein kinase C inhibitors reversed the decrease in beta-adrenoceptor number. PMA plus ionophore or interleukin-2 but not PMA alone were able to induce beta-adrenoceptor down-regulation accompanying cellular proliferation. These results showed that the intracellular signals triggered during lymphocyte activation are involved in beta-adrenoceptor down-regulation and it would represent the loss of a mechanism that exerts negative neuroimmune control of cellular proliferation.

Reduced number and coupling of beta-adrenergic receptors in a modified S49 mouse lymphoma cell line.

Long-term culture of S49 wild-type cells in medium containing a high concentration of fetal calf serum leads to a modified (S49m) cell line with a reduced number of beta-adrenergic receptors (R). These S49m cells with a higher rate of proliferation were unable to respond to the beta-adrenergic agonists isoproterenol (ISO) and epinephrine as analysed by measuring adenylate cyclase (ac) activity on purified membranes of these cells. Additionally, no accumulation of cyclic AMP was obtained on S49m intact cells upon stimulation with beta-agonists. Nevertheless, S49m cells were able to respond significantly to the direct activation of the stimulatory guanine nucleotide binding (Gs) protein by aluminium tetrafluoride and sodium fluoride, and to the stimulation of another receptor coupled to the ac system through a Gs protein, by prostaglandin E1 (PGE1). When cloning S49m cells, similar results were obtained upon stimulation with ISO and PGE1 and the cloned cells express the same thy 1.2 and class Id molecules as do S49 cells. The study of S49m cells indicates that they are a beta-adrenergic R-deficient variant distinct from the other variants described for S49 cells.