DIFFERENT SENSITIVITIES OF NEUTROPHIL RESPONSES TO A SELECTIVE PROTEIN-KINASE-C INHIBITOR, RO-31-8425 - REDUNDANCY IN SIGNAL-TRANSDUCTION

Previous studies implicating a role for protein kinase C (PKC) in medi ating stimulation of cellular responses by physiological agonists have relied on use of non-specific inhibitors or direct stimulation of PKC by phorbol esters. However, much of this evidence is questionable. He re, we have investigated the effects of a potent and selective PKC inh ibitor, Ro 31-8425, on three different responses of human neutrophils stimulated by either a physiological agonist, C5a, or a phorbol ester, PMA. The responses studied were superoxide generation, collagenase se cretion and adhesion to endothelial cells. In each case, the PMA-stimu lated response was more sensitive to inhibition than the C5a-stimulate d response. Even the PMA-stimulated responses differed in their sensit ivity to inhibition, with superoxide production being the most sensiti ve and adhesion the least sensitive. The different sensitivities of th e PMA stimulated responses suggest that, although activation of PKC st imulates the responses, either different degrees of activation or diff erent isozymes are required for the different responses. The lower sen sitivity of the C5a-stimulated responses in each case suggests that PK C activation, if needed at all, is not rate Limiting in these signal t ransduction pathways. These results emphasize the redundancy in intrac ellular signal transduction. Copyright (C) 1997 Elsevier Science Inc.