Natural killer cell reactivity: regulatory interactions and among phorbol ester, interferon, cholera toxin, and retinoic acid.

This paper demonstrates that the expression of mouse and human natural killer cells is modulated by several molecules with widespread biologic regulatory potential: the potent tumor promoter phorbol-12-myristate-13-acetate, retinoic acid, and cholera toxin, as well as by interferon. The tumor-promoting phorbol ester, but not nontumor-promoting structural analogs, inhibited both mouse and human natural killer cell activity. Phorbol ester inhibited both spontaneous and interferon-augmented mouse natural killer cell activity, but the effects on the latter varied considerably with the sequence of the treatments. Human peripheral blood lymphocytes and subpopulations enriched for large granular lymphocytes that account for human natural killer cell activity showed a more variable response to phorbol ester: with some donors, spontaneous and interferon-boosted natural killer cell activities were inhibited, but with others only the boosted activity was affected. Retinoic acid was found to enhance natural killer cell activity, and this augmented activity was also inhibited by the tumor promoter. Combined treatment with retinoic acid and interferon produced less augmentation than either agent alone. Cholera toxin strongly inhibited spontaneous and augmented natural killer cell activity. However, subunits A or B of cholera toxin lacked the capacity to inhibit spontaneous or interferon-augmented NK activity. Our results indicate that natural killer cell activity is subject to regulation by a variety of physiologically active agents. It is of both biologic interest and of potential significance that a tumor promoter inhibits natural killer cell activity whereas retinoic acid, a tumor preventive agent, enhances natural killer cell activity. We discuss the possible nature of the interactions among these agents and the potential in vivo relevance of the observed effects of the tumor promoter.