The inhibition of neutrophil responsiveness caused by phorbol esters is blocked by the protein kinase C inhibitor H7

Abstract

The relationship between the inhibition of neutrophil responsiveness to chemoattractants caused by preincubation with phorbol esters and the activation of protein kinase C was investigated using the protein kinase antagonist H7. The latter compound was found to inhibit the phosphorylation of the 50 kDa protein kinase C substrate stimulated by phorbol 12-myristate 13-acetate (PMA). On the other hand, H7 was found not to affect the quin2 and secretory responses of the neutrophils to fMet-Leu-Phe and leukotriene B4. In addition, pretreatment of the cells with H7 blocked the ability of PMA to inhibit the latter two responses to the addition of the chemoattractants. Taken together, these results provide strong evidence for the involvement of protein kinase C in the inhibition of neutrophil--and probably also other cells--responsiveness brought about by preincubation with phorbol esters. Additionally, they invite a reevaluation of the role of protein kinase C in the excitation-response coupling sequence of these cells directed more towards a negative, modulatory, role than that of a critical element in its initiation.