Farnesylcysteine derivatives can initiate or inhibit superoxide (O-2(-)) release in neutrophils. The mechanism by which one of these derivatives, farnesyl thiotriazole (FTT), initiates O-2(-) release in neutrophils is the subject of this paper. Treatment of guinea pig neutrophils with FTT results in the rapid release of O-2(-) by a route shown to be independent of the chemotactic peptide N-formyl-Met-Leu-Phe (fMLP) receptor. The signal transduction pathway utilized by the chemoattractant fMLP is generally accepted as the paradigm for receptor-mediated stimulation of O-2(-) production. Antagonists of fMLP had no effect on FTT-induced O-2(-) release, and pretreatment of neutrophils with fMLP had no effect on the ability of FTT to trigger further O-2(-) generation. In fact, FTT behaves like a typical protein kinase C (PKC) activator. It promotes phosphorylation of the 47-kDa subunit of the NADH oxidase complex (p47-phox) in neutrophils, and this phosphorylation is specifically blocked by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), an antagonist of PKC. FTT is also shown to activate PKC in vitro in a specific and saturable fashion. FTT is approximately equipotent with (S)-diolein, a physiologically relevant activator of this kinase. FTT represents a new, and quite novel, structure for a PKC activator. PKC activators include diglycerides and the structurally diverse tumor promoters.
