Different Sensitivities of Neutrophil Responses to a Selective Protein Kinase C Inhibitor, Ro 31-8425; Redundancy in Signal Transduction

Abstract

Previous studies implicating a role for protein kinase C (PKC) in mediating 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. Here, we have investigated the effects of a potent and selective PKC inhibitor, 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 secretion and adhesion to endothelial cells. In each case, the PMA-stimulated response was more sensitive to inhibition than the C5a-stimulated response. Even the PMA-stimulated responses differed in their sensitivity to inhibition, with superoxide production being the most sensitive and adhesion the least sensitive. The different sensitivities of the PMA stimulated responses suggest that, although activation of PKC stimulates the responses, either different degrees of activation or different isozymes are required for the different responses. The lower sensitivity of the C5a-stimulated responses in each case suggests that PKC activation, if needed at all, is not rate limiting in these signal transduction pathways. These results emphasize the redundancy in intracellular signal transduction.