Prostaglandin synthesis inhibitors potentiate the BCG-induced augmentation of natural killer cell activity

We have previously reported that BCG induced a rapid and intense augmentation of murine peritoneal natural killer (NK) cell activity. A requirement for macrophages and for soluble NK-enhancing factors was also demonstrated. In the present report we show that BCG-induced peritoneal macrophages secreted large amounts of prostaglandin E₂ (PGE₂). In vitro, PGE₂ inhibited both normal splenic NK cells and BCG-induced peritoneal NK cells at concentrations between 10^-9 and 10^-5 M, in contrast to the inactive PGF(2α) isomer. BCG-induced PGE₂ synthesis was inhibited in vivo with the prostaglandin cyclo-oxygenase inhibitors indomethacin and aspirin. These drugs concommitantly potentiated the BCG-induced augmentation of peritoneal NK cells, although they had only marginal effects on normal NK activity in vivo or in vitro. Pretreatment of BCG-induced peritoneal exudate cells (BCG-PEC) in vitro with indomethacin or aspirin also potentiated the augmentation of normal splenic NK cells by BCG-PEC supernatants in vitro. With these inhibitors of prostaglandin synthesis, there was an inverse correlation, both in vitro and in vivo, between the levels of PGE₂ secreted by BCG-induced macrophages and the augmentation of NK activity. Thus, the macrophage appears to play a central role in the regulation of NK activity in BCG-infected mice by way of secreting NK-ehancing factors and NK-inhibiting factors, including PGE₂. Pharmacologic intervention to manipulate NK activity via control of the secretion of macrophage factors may prove useful in further enhancing the immunotherapeutic effects of BCG.