Induction of nitric oxide synthase activity in phagocytic cells inhibited by tricyclodecan‐9‐yl‐xanthogenate (D609)

Abstract

The synthesis of nitric oxide (NO) by immune‐stimulated murine phagocytic cells (J774) and the modulation of this synthesis by tricyclodecan‐9‐yl‐xanthogenate (D609), a specific inhibitor of phosphatidylcholine‐specific phospholipase C (PC‐PLC), was investigated. D609 dose‐dependently suppressed production of NO, as measured by the release of nitrite and nitrate, in response to lipopolysac‐charide (LPS) and interferon‐γ (IFN‐γ) in intact cultured cells with an IC50 of approximately 20 μg ml−1. D609 at 40 μg ml−1 completely abrogated immune‐stimulated nitrite production. The inhibitory effects of D609 on nitrite production were time‐dependent and restricted to the first 18 h post‐stimulation. D609 did not inhibit nitrite production in the cytosol of immune‐stimulated phagocytes. These findings indicate that the xanthogenate, D609, is a potent inhibitor of the induction of NO‐synthase activity in immune‐stimulated phagocytes. Furthermore, since D609 has been demonstrated to inhibit PC‐PLC specifically, our findings suggest that the activation of this enzyme by LPS and IFN‐γ is a proximal step in the signal transduction of inducible NO‐synthase in phagocytic cells. 1994 British Pharmacological Society