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Role of Cyclic Adenosine 3',5'-Monophosphate in Lymphocyte Mitogenesis

From the United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21701 and the Veterans' Administration Hospital, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15240

Abstract

For assessment of the role of cyclic adenosine 3',5'-monophosphate (cAMP) in lymphocyte mitogenesis, adenylate cyclase activity, cAMP content, ³H-thymidine (³H-THY) incorporation, and blast transformation were examined in lymphocytes incubated with mitogenic agents, and with prostaglandins, cholera toxin, or theophylline. When tested over a wide dose range with mouse spleen cells, the mitogens phytohemagglutinin-P (PHA-P), staphylococcal enterotoxin B (SEB), concanavalin-A (CON-A), and endotoxin did not stimulate adenylate cyclase activity or increase cellular cAMP content. Similarly, in human lymphocytes, neither SEB, CON-A, nor mitogenic doses of PHA-P altered cellular cAMP levels. A rapid increase in human lymphocyte cAMP was noted in response to high doses of PHA-P, but such doses resulted in little induction of ³H-THY incorporation compared to lower doses that were ineffective in elevating cAMP. Further, PGE₁, cholera toxin, and theophylline, agents which all significantly increased lymphocyte cAMP content, uniformly suppressed both basal and mitogen-induced ³H-THY incorporation and blast transformation in a dose-related manner.

The inhibitory effects of PGE₁, cholera toxin, and theophylline on mitogen induced ³H-THY incorporation were time-dependent. After a 36-hr exposure of mouse spleen cells to CON-A increases in cellular cAMP no longer inhibited subsequent DNA synthesis, perhaps owing to the fact that those metabolic events influenced by cAMP were already completed in the majority of mitogen-activated cells by 36 hr. Moreover, washing mouse spleen cells which had been concomitantly incubated with CON-A and with PGE₁ or theophylline for periods up to 36 hr abolished the inhibitory actions of the latter agents on ³H-THY incorporation. It seems possible from these results that elevated cellular cAMP levels may only delay, by a reversible process, the flow of mitogen-activated lymphocytes through their growth cycle and that lymphocytes remain susceptible to such inhibition for only a finite period after stimulation with mitogens.

Footnotes

¹ Address reprint requests to: F. R. DeRubertis, V. A. Hospital, University Drive C, Pittsburgh, Pennsylvania 15240.

² Present address: United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21701.

³ Present address: Gerontology Research Center, Baltimore City Hospital, Baltimore, Maryland 21214.

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