Inhibition of human natural cytotoxicity by macromolecular antiproteases

Human natural cell-mediated cytotoxicity is inhibited by macromolecular protease inhibitors. Human plasma α ₁antiproteases are more effective than the plant antiproteases lima bean trypsin inhibitor and soybean trypsin inhibitor for reduction of cytotoxicity to the 'slow' targets T24 human bladder carcinoma and NKI-1 melanoma. This inhibition of natural cytotoxicity is more readily demonstrable in serum-free medium containing crystalline bovine serum albumin than in medium containing fetal calf serum. Although electrophoretically homogeneous plasma α ₁antitrypsin inhibits natural cytotoxicity, partially purified α ₁antitrypsin preparations that contain several α ₁proteins are more inhibitory at equivalent trypsin inhibitory capacities. Partially purified α ₁antichymotrypsin with no antitrypsin activity is an extremely potent inhibitor. Thus, it seems likely that several of the plasma antiproteases, including α ₁antitrypsin and α ₁antichymotrypsin, are capable of influencing natural cytotoxicity. These data indicate that serine-dependent proteases have a critical role in triggering and/or effecting cell-mediated cytolysis. Furthermore, since α ₁antichymotrypsin and α ₁antitrypsin are acute phase proteins, the increase in plasma concentration or turnover rates of the proteins could influence natural killer cell activity in vivo.