Evidence for Cyclic GMP and Calcium Mediation of Lymphocyte Activation by Mitogens

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Abstract
The results of 47 experiments indicate that the lectin mitogens, PHA and Con A, increase cyclic GMP (cGMP) levels in human peripheral blood lymphocytes and their incubation medium 2- to 9-fold within 10 min of stimulation. At concentrations supraoptimal for the induction of proliferation, Con A, but not PHA, induces progressive increases in cAMP and lesser increases in cGMP. Succinylated Con A (S-Con A) does not exhibit inhibition of proliferation up to concentrations of 250 µg/ml and correspondingly does not produce the cAMP increases observed with native Con A. PHA and both forms of Con A induce modest increases in cGMP in the absence of calcium and no increases in the presence of EGTA. After preexposure to Con A in the absence of calcium, the addition of calcium produces increases in cGMP. The data are consistent with the interpretation that mitogen-induced increases in lymphocyte cGMP are totally Ca2+-dependent, yet only in part dependent on extra-cellular Ca2+. The interpretation is confirmed with a divalent cation ionophore A23187, which was shown to induce lymphocyte proliferation in close association with Ca2+-dependent increases in cGMP and at higher concentrations to inhibit the mitogenic effects in association with Mg2+-dependent increases in cAMP. Dose-response curves for each agent showed that this capacity to increase cGMP levels was correlated with the optimal mitogenic concentration as determined by assay of DNA synthesis. The data are consistent with the postulate that cGMP participates in the positive aspects of mitogen action and that cAMP participates in the inhibitory aspects. It is concluded that coparticipation of cGMP and Ca2+ as essential mediators of the mitogenic signal is a sound hypothesis.

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