Trichodion, a new inhibitor of inflammatory signal transduction pathways from a Trichosporiella species

In a search for new inhibitors of the IFN-gamma mediated signal transduction in HeLa S3 cells using secreted alkaline phosphatase (SEAP) as reporter gene, the novel pyran-dione trichodion was isolated from fermentations of the imperfect fungus Trichosporiella sp. 20-95. The compound inhibits the IFN-gamma mediated expression of the reporter gene with IC50 values of 21-42 mu M (5-10 mu g/ml). The NF-kappa B and AP-1 mediated expression of the reporter gene are inhibited with IC50 values of 42-84 mu M (10-20 mu g/ml) and 21 mu M (5 mu g/ml) respectively. Western blotting with COX-2 and NOS II antibodies showed that the expression of both proinflammatory enzymes is almost completely inhibited at 21-42 mu M (5-10 mu g/ml) in LPS/IFN-gamma stimulated J774 mouse macrophages. Studies on the mode of action of the compound revealed that the inhibition of the NF-kappa B dependent pathway is due to the stabilization of the I kappa B protein and the inhibition of the IFN-gamma dependent signaling is caused by an inhibition of the phosphorylation of the STAT1 alpha transcription factor. (C) 2000 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.