Retinoic Acid Inhibition of the Comitogenic Action of Mezerein and Phorbol Esters in Bovine Lymphocytes

12-O-TetradecanoylphorboM 3-acetate (TPA) is an effective comitogen in phytohemagglutinin-treated bovine lymphocytes. Concurrent addition of 10-8 m TPA gives a greater than 6-fold increase in DNA synthesis over cultures treated with the lectin alone. The delayed addition of phorbol ester, relative to the start of the lectin treatment, eliminates this synergistic action. Structure-function studies show that the comitogenic activity of different phorbol diesters runs parallel to their tumor-promoting activity. A nontoxic level (50 μ m) of retinoic acid selectively antagonizes this synergistic effect of phorbol ester. This inhibitory action requires the near-concurrent addition of retinoic acid with TPA. In contrast, the TPA-me-diated induction of RNA and protein synthesis is unaffected by retinoic acid. A number of natural and synthetic retinoids were evaluated; none were as inhibitory as was retinoic acid. Lymphocyte cultures appear to provide a useful system for exploring the mechanisms of action of both TPA and retinoic acid.