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Differential Activation and Inhibition of Lymphocyte Proliferation by Phorbol Esters, Mezerein, Teleocidin, and Okadaic Acid¹

Department of Molecular and Cell Biology, The Pennsylvania State University, University Park, Pennsylvania 16802

Lymphocytes can be stimulated to proliferate in vitro by mitogens such as concanavalin A. The tumor-promoting phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) can enhance this proliferation, partly because of an increase in interleukin 2 (IL-2) production. However, if lymphocytes are treated with TPA for 24 h before concanavalin A exposure, IL-2 production and proliferation are depressed. The target of the action of TPA is protein kinase C, which is activated after a short exposure but down-regulated after a longer one. This study was designed to determine if the modulation of IL-2 was separable from the modulation of protein kinase C. When phorbol esters phorbol 12-retinoate-13-acetate, phorbol 12,13-dibutyrate, 12-deoxyphorbol 13-phenylacetate, and 12-deoxyphorbol 13-phenylacetate-20-acetate, as well as nonphorbol tumor promoters mezerein, telocidin, and okadaic acid, were tested, all but okadaic acid reproduced the effects of TPA. However, 12-deoxyphorbol 13-phenylacetate and 12-deoxyphorbol 13-phenylacetate-20-acetate were required at nearly 100-fold higher concentrations than TPA to suppress IL-2 production, suppress mitogenesis, and cause down-regulation of protein kinase C. A comparison of structures indicated that an R group at the 12-position was less important for IL-2 production and mitogenesis than for down-regulation of protein kinase C and the suppression of mitogenesis. In no case was the modulation of protein kinase C separated from the effects on IL-2 production and proliferation.

¹ This work was supported mainly by Grant CA24385 from the National Cancer Institute to A. M. M. and partly from NASA, NAGW 1196.

² To whom requests for reprints should be addressed.

Received 4/18/90. Accepted 10/ 4/90.

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