The Effect of Agents Which Modulate Levels of the Cyclic Nucleotides on Human Lymphotoxin Secretion and Activity in Vitro

Abstract

The ability of concanavalin-A (Con-A) to activate lymphocytes to secrete human lymphotoxin (LT) was tested in the presence of agents known to modify the intracellular levels of cyclic nucleotides (cAMP and cGMP). Lymphocytes were treated with these agents at different stages of activation: (1) during the first encounter with mitogens, and (2) after they had been fully activated and were restimulated. Two agents, Dibutyryl cAMP and theophylline, dramatically inhibit the amount of LT secreted during both "primary" and "secondary" activation by Con-A. In contrast, DL-isoproterenol had a weak effect during primary activation, but greatly reduced the level of LT secreted during secondary activation. Agents which affect the intracellular level of cGMP were also tested. Imidazole had no effect on LT secretion by either primary or secondary Con-A activated cells. In contrast, carbamyl choline greatly reduced LT secretion to a level comparable to Dibutyryl cAMP and theophylline. All agents tested protected, to some degree, the sensitive a-L cell against LT-induced destruction in vitro. Agents which affect the levels of cyclic nucleotides affect both the effectiveness of the aggressor cell and the sensitivity of the target cells in vitro.Cyclic nucleotides have been shown to have an important role in the regulation of cellular biosynthesis and metabolism (19) in inflammation and immunity (1). They appear to be important in both immediate and delayed hypersensitivity reactions. Production and/or secretion of antibodies by B lymphocytes is reduced when intracellular levels of cyclic adenosine 3',5'-monophosphate are raised (16,23). Destruction of cells by immune lymphocytes activated by contact with target cell antigens, and in vitro measure of cell-mediated immunity, is suppressed when the effector lymphocytes are treated with pharmacologic drugs which increase the adenosine 3',5'-monophosphate (cAMP) level (14,21,22) . On the other

Factors affecting E-rosette forming ability in peripheral lymphocytes of insulin dependent diabetics

“…Pancreatic hormones show opposite effects in vitro: insulin can restore E-rosette forming ability of diabetic lymphocytes in the presence of glucose, while glucagon exerts an inhibitory effect on normal lymphocytes. These actions may be due to the hormonal modulation of intracellular nucleotides: it is widely recognized that substances inducing a rise of cellular cAMP enhance T-cell function, while agents promoting a rise in intracellular cAMP seem to inhibit E-rosette forming ability [25,26,27]. However, we have not been able to show any difference in the cAMP content of normal and diabetic human lymphocytes, in contrast with the reports of increased cAMP content of mononuclear cells from diabetic rats [28].…”

Selective phosphodiesterase inhibitors for the treatment of bronchial asthma and chronic obstructive pulmonary disease

“…In addition to its ability to inhibit mitogen‐induced and T‐cell antigen receptor (CD3)‐mediated proliferation of T lymphocytes in vitro [50, 51], theophylline enhances the suppression of autologous cell proliferation in mixed lymphocyte preparations [52], a phenomenon that is reflected by the induction in theophylline‐treated asthmatic subjects of an increased population of suppressor T cells [53, 54]. Theophylline also reduces cytokine release from T lymphocytes in vitro [51, 55], which may imply further actions on cytokine‐dependent functions of other leucocytes in vivo .…”

Identification of membrane-associated lymphotoxin (LT) on mitogen-activated human lymphocytes using heterologous anti-LT antisera in vitro

“…The finding that LT can exist on activated lymphocyte surfaces is a new concept, for in the past, LT has only been considered as a "soluble-phase" mediator (2)(3)(4)(5)(6). This conclusion has grown from experiments which show that LT release (7)) as well as MIF release (8), is suppressed by agents which inhibit protein synthesis or secretory processes (9) or alter levels of cyclic nucleotides (CAMP) (10).…”