Antibody-dependent cell-mediated cytotoxicity in humans. III. Effect of protease inhibitors and substrates.

Different classes of protease inhibitors and substrates were tested for their effect on the ability of human lymphocytes to mediate antibody-dependent cytotoxicity (Ab CMC). All the inhibitors tested (serine esterase inhibitors, chloromethyl ketone derivatives of tosyl-amino acids, synthetic protease substrates), except for the naturally occurring protease inhibitors (derived from soybean, lima bean, and porcine pancreas), were able to suppress, or to reduce insignificantly, the cytotoxicity. In the absence of a direct demonstration of an esterase activity, sensitive to the action of the inhibitors in the effector lymphocytes, careful controls were used to restrict the possibility that some nonspecific effect of the drugs was being interpreted. Particularly, the dependence of the inhibition of cytotoxicity as an effect of drugs on membrane transport mechanisms or on energy metabolism was excluded. The similarity between results obtained with compounds of different chemical characteristics and different molecular mechanisms of action supports a specific effect of the inhibitor on cellular esterase(s) or possibly protease(s). The fully reversible inhibition obtained with serine esterase inhibitors suggests that the relevant enzymes are activated only after effector-target cell interaction; the irreversible effect of chloromethyl ketone derivatives, however, does not allow the participation of already activated enzymes to be excluded. The results presented in this study on the probable role of cellular esterases, on cation requirement and on the sequence of biochemical steps in Ab CMC add a new element to the analogy between this cellular phenomenon and different types of cytotoxicity or other immunologically induced cellular reactions, suggesting that the biochemical mechanisms of cytotoxicity may partly reflect a common pattern of cellular response to external stimuli.