Adenosine 3':5'-cyclic monophosphate (cyclic AMP) has been shown to have an antimitotic role in various cell types, and it has been hypothesized that'a decrease of cyclic AMP concentration in the cell initiates or permits cell division. This hypothesis has been evaluated with respect to clonal proliferation of lymphocytes. Two potent mitogenic agents, phytohemagglutinin and concanavalin A, which induce thymic-dependent lymphocytes to undergo clonal' proliferation, were examined for their ability to initiate proliferation and to alter the concentrations of cyclic AMP and guanosine 3':5'-cyclic monophosphate (cyclic GMP) in purified human peripheral blood-lymphocytes. Optimal mitogenic concentrations of phytohemagglutinin and concanavalin A produced 10-to 50-fold 'increases in the concentration of lymphocyte cyclic GMP within the first 20 min of'exposure to the mitogens. No changes were seen in the concentration of cyclic AMP after stimulation with either mitogen in purified form. Increases of less than 2-fold in 'the concentration of lymphocyte cyclic AMP observed with a less purified preparation of phytohemagglutinin could be attributed to the agglutinating rather than the mitogenic properties of the mitogen. A revised hypothesis' is presented in which a temporally discrete rise in lymphocyte cyclic GMP concentration is viewed as an active signal to induce proliferation, while the elevation of cyclic AMP concentration in these cells is viewed as a regulatory influence that limits or inhibits mitogenic action.The lymphocyte, a cell whose normal functions include, clonal proliferation after stimulation by antigen, provides a model for studying the biochemical events related to initiation of cellular division. Mitogens, such as phytohemagglutinin (PHA) and concanavalin A (Con A), have been used to induce clonal proliferation in lymphocytes, particularly those derived from the thymus. Several experiments (1-6) have been performed in which the relationship between cyclic AMP concentration and mitogen-induced lymphocyte division has been investigated. The results indicate (a) that cyclic AMP itself does not significantly stimulate division of lymphocytes in the resting phase ("Go" or "G1" phase) of the cell cycle (1), (b) that increases in cyclic AMP concentration resulting from stimulation by hormones and polynucleotides do not induce lymphocytes to divide (2, 3), and (c) that agents that promote increases in Iymphocyte cyclic AMP concentration inhibit mitogen-induced clonal proliferation (4-6).Abbreviations: PHA, phytohemagglutinin; Con A, concanavalin A.t To whom reprint requests should be addressed: Box 494 Mayo, University of Minnesota Hospitals, Minneapolis, Minn. 55455.In contrast to the foregoing is the observation that high concentrations of PHA can induce small increases in the amounts of cyclic AMP in lymphocytes (4). These observations have been interpreted as support for the concept that PHA exerts its mitogenic effects through an increase in cellular cyclic AMP concentration. Support for the o...

Phorbol myristate acetate (pma) is a potent mitogen for human peripheral blood lymphocytes (PBL) comparable to phytohemagglutinin (PHA) in potency. Inactivation of PHA-responsive lymphocytes by 5'-bromodeoxyuridine and light treatment left the PMA response intact and nice versa. Experiments separating lymphocytes by rosetting with sheep erythrocytes (SRBC) demonstrated that the PMA-responsive lymphocytes segregate with those that have a high affinity for SRBC to a greater than PHA- or concanavalin A (Con A)-responsive cells. These results indicate that a PMA-responsive population in human peripheral blood resides within the T-lymphocyte population and appears to have a high affinity for SRBC and to be distinct from that responding to PHA and Con A. PMA may be useful clinically to assay the size and function of the high affinity or "active" rosette population.

Thymic epithelial cells (TEC) are known to secrete thymic hormones that influence maturation of T lym- [2884][2885][2886][2887][2888][2889][2890] showed that interleukin 1 (IL-i) in vivo stimulates zinc uptake by the thymus. Both the a and J forms of IL-1, which stimulate proliferation of human TEC, also stimulate their uptake of zinc in vitro, and this latter stimulation is both dependent and independent of proliferation. Zinc induces zinc accumulation without proliferation. Two other stimulants of proliferation, bovine pituitary extract and epidermal growth factor, stimulate zinc uptake by TEC, but only in a manner dependent on proliferation. Utilizing in situ hybridization, we show that the IL-1 a and P forms and zinc induce metallothionein mRNA expression in TEC. Metallothionein is thought to be involved in the transfer of zinc to thymulin. IL-1 was shown to stimulate the secretion of thymulin as measured both by its ability to smulate induction of IL-2 receptor-positive lymphocytes from human peripheral blood lymphocytes and by the azathioprinesensitive rosette assay. In addition, the zinc-thymul complex in the presence, but not absence, of IL-1 stimulates nuclear protein kinase C in isolated lymphocyte nuclei. IL-1 apparently regulates the synthesis or secretion and delivery of zincthymulin complex to the T-lymphocyte system.

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