Phorbol esters induce synthesis of thromboplastin activity in human monocytes

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Abstract
12-O-Tetradecanoylphorbol-13-acetate (TPA), phorbol-12,13-diacetate and phorbol-12,13-didecanoate were all potent inducers of thromboplastin activity in human monocytes in vitro; 4.alpha.-phorbol-12,13-didecanoate and 4.alpha.-phorbol had no such effect. A concomitant increase in titrable apoprotein III antigen was found (apoprotein III is the protein component of thromboplastin). The increase was inhibited by cycloheximide and actinomycin D and partly by .alpha.-amanitin. The increase of thromboplastin activity was most likely due to synthesis de novo of apoprotein III. The response was approximately halved in the absence of serum or Ca2+. Retinol had a weak inhibitory effect and retinoic acid was inhibitory only at concentrations that also induced signs of cytotoxicity. TPA caused an initial rise in monocyte cAMP concentration of .apprx. 90-120 min duration. No increase in 45Ca2+ influx was induced over 2 h. Good correlation exists between induction of apoprotein III synthesis in monocytes in vitro and mouse skin-tumor promotion in vivo by the various phorbol derivatives. Substances inactive in tumor promotion do not induce the synthesis of apoprotein III. General activating and cytotoxic effects of TPA were monitored by determining release of lysozyme, .beta.-glucuronidase and lactate dehydrogenase.