FARNESYL THIOTRIAZOLE, A POTENT NEUTROPHIL AGONIST AND STRUCTURALLY NOVEL ACTIVATOR OF PROTEIN-KINASE-C

Farnesylcysteine derivatives can initiate or inhibit superoxide (O-2(- )) release in neutrophils. The mechanism by which one of these derivat ives, farnesyl thiotriazole (FTT), initiates O-2(-) release in neutrop hils 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 b e independent of the chemotactic peptide N-formyl-Met-Leu-Phe (fMLP) r eceptor. The signal transduction pathway utilized by the chemoattracta nt fMLP is generally accepted as the paradigm for receptor-mediated st imulation of O-2(-) production. Antagonists of fMLP had no effect on F TT-induced O-2(-) release, and pretreatment of neutrophils with fMLP h ad no effect on the ability of FTT to trigger further O-2(-) generatio n. In fact, FTT behaves like a typical protein kinase C (PKC) activato r. It promotes phosphorylation of the 47-kDa subunit of the NADH oxida se complex (p47-phox) in neutrophils, and this phosphorylation is spec ifically blocked by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H- 7), an antagonist of PKC. FTT is also shown to activate PKC in vitro i n a specific and saturable fashion. FTT is approximately equipotent wi th (S)-diolein, a physiologically relevant activator of this kinase. F TT represents a new, and quite novel, structure for a PKC activator. P KC activators include diglycerides and the structurally diverse tumor promoters.