Inhibition of the phagocytosis-induced respiratory burst by the fungal metabolite wortmannin and some analogues.

The sterol-like fungal metabolite wortmannin and a number of natural and chemically-derived analogues were found to block the induction of the respiratory burst during phagocytosis. 17-Hydroxy wortmannin, the most active compound tested, showed a 50% inhibition of the burst in neutrophils and mononuclear phagocytes at concentrations ranging between 0.8 and 17 nM, while wortmannin itself was about half as potent. Chemical derivation showed that a furane structure between ring A and B with adjacent carbonyl functions is essential for activity. At concentrations that entirely prevented superoxide or hydrogen peroxide production, the wortmannins were not cytotoxic and did not inhibit phagocytosis. At even higher concentrations (10 microM), 17-hydroxy wortmannin had no effect on the NADPH oxidase, once activated. This suggests that the wortmannins interfere with the signal transduction sequence initiated by the particulate stimulus and leading to the activation of the respiratory burst oxidase.