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The Role of Cyclic 3',5' Adenosine Monophosphate in the Specific Cytolytic Activity of Lymphocytes^1,2,

From the Department of Medicine of Johns Hopkins University and the O'Neill Research Laboratories of the Good Samaritan Hospital, Baltimore, Maryland and the Department of Medicine of the University of California Medical Center, San Francisco, California

Abstract

The in vitro destruction (⁵¹Cr release) of DBA/2 mastocytoma cells by lymphocytes from immune C57BL mice has been used as a system to study the relationship between lymphocyte cyclic 3',5'-adenosine monophosphate (cAMP) levels and cytolytic activity. It was established that there is a direct correlation between increased intracellular levels of cAMP and the inhibition of cytolytic activity of a lymphocyte population.

Treatment of lymphocytes with adenyl cyclase stimulating agents (histamine, isoproterenol and prostaglandins E₁ and E₂) caused increases in cAMP levels and inhibited cytolytic activity. The time course of the increase in cAMP content following exposure to drug paralleled closely the time course of inhibition of cytolytic activity. The effect of isoproterenol on both cAMP content and cytolytic activity was short lived; the prostaglandins produced longer lasting effects on both systems.

Theophylline, which inhibits the enzymatic degradation of cAMP also inhibited cytolysis. This inhibitory effect was at least additive to that produced by isoproterenol.

The specificity of the relationship between intracellular cAMP levels and cytolytic activity was shown by the following observations. 1) Cyclic AMP and dibutyryl cyclic AMP inhibited lymphocyte activity. 5'-AMP at comparable concentrations did not. 2) The prostaglandins PGE₁ and PGE₂ both increased cyclic AMP content and consistantly inhibited lymphocyte-mediated cytolysis. Prostaglandin PGF 1 was inactive in both systems. 3) Propanolol, a -adrenergic blocking agent, specifically prevented the effect of isoproterenol, a -adrenergic agonist, on both cyclic AMP and cytolytic activity, but did not prevent the effect of the prostaglandins or histamine in either system.

These results suggest that cAMP occupies a central modulatory role in the expression of cytolytic activity by lymphocytes.

Footnotes

¹ This is communication 23 from the O'Neill Research Laboratories.

² This work was supported by Grants AI 10280 (C. S. H.), AI 7290, AI 8290 (L. M. L.) and HE 09964 (H. R. B.).

³ Dr. Bourne is an established investigator of the American Heart Association.

⁴ Dr. Lichtenstein is a recipient of a research career development award from the National Institute of Allergy and Infectious Diseases.