Abstract
Pharmacological agents known to modify intracellular levels of adenosine and guanosine 3′,5′-cyclic monophosphate (cAMP and cGMP) were tested for their ability to influence the formation of leukocyte migration inhibitory factor (LIF) by human lymphocytes stimulated by phytohemagglutinin (PHA). The cAMP-elevating agents, papaverine (3 × 10 −5 M) and dibutyryl cAMP (10 −4–10 −6 M), reversibly inhibited LIF production. The effect of dibutyryl cAMP was dose related and could be reversed by simultaneous addition of dibutyryl cGMP. Experiments in which lymphocytes were treated with dibutyryl cAMP at different stages of activation showed that: (i) increased levels of cAMP interfered with LIF synthesis and/or secretion rather than the initial PHA-induced membrane events; and (ii) the period in which the lymphocytes were sensitive to cAMP-induced blocking of LIF formation was limited to the early G 1 phase of the cell cycle; i.e., within 22 hr after mitogen activation. The ability of dibutyryl cAMP and papaverine to abrogate LIF production was not due to a general inhibitory effect of these agents on cellular protein synthesis or secretion. In contrast, both drugs had a weak positive effect on the release of [ 3H]leucine-labeled protein from PHA-activated cells. In spite of the fact that cGMP-elevating agents (10 −4 M dibutyryl cGMP, 10 −5 M carbamylcholine, and 10 −5 M imidazole) increased cellular protein synthesis and secretion in unstimulated mononuclear cells, they did not by themselves trigger LIF production, and they did not inhibit or enhance LIF production by PHA-activated cells.
Published Version
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