Wortmannin Inhibits the Production of Reactive Oxygen and Nitrogen Intermediates and the Killing of theSaccharomyces Cerevzsaeby Isolated Chicken Macrophages

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Abstract
The direct effects of wortmannin (0 to 1280 nM) on several functions in cultured macrophages isolated from Sephadex-elicited Leghorn chicken peritonea were studied. Under concentrations not affecting cell viability, wortmannin, as low as 5 nM, inhibited lipopolysaccharide (LPS)-induced nitric oxide production (P < 0.01). However, wortmannin (as high as 1280 nM) exposure 5 hours post LPS induction had no effect on nitric oxide production in macrophages, indicating a blockade of LPS-induction of a signaling pathway related to nitric oxide formation. Phorbol myristate acetate (PMA)-induced superoxide production was only inhibited (P < 0.001) by concurrent exposure to 1280 nM wortmannin. Prior exposure to 160 nM and higher of wortmannin for 24 hours reduced the average number of yeast cells ingested by or attached to a single macrophage (P < 0.001) and the ability of the macrophage to kill the baker's yeast (P < 0.05), while wortmannin itself did not affect the yeast. These data provide direct evidence for macrophages being the target cell of wortmannin and further support the notion that impaired macrophage functions are responsible for the immunosuppressive effect of wortmannin previously observed in birds.