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 IC(50) values of 21-42 microM (5-10 microgram/ml). The NF-kappaB and AP-1 mediated expression of the reporter gene are inhibited with IC(50) values of 42-84 microM (10-20 microgram/ml) and 21 microM (5 microgram/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 microM (5-10 microgram/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-kappaB dependent pathway is due to the stabilization of the IkappaB protein and the inhibition of the IFN-gamma dependent signaling is caused by an inhibition of the phosphorylation of the STAT1alpha transcription factor.
Erkel
G
G
Institut für Biotechnologie und Wirkstoff-Forschung e.V., Erwin-Schrödinger-Str. 56, D-67663, Kaiserslautern, Germany. erkel@ibwf.uni-kl.de
D000818:Animals; D001483:Base Sequence; D051546:Cyclooxygenase 2; D017931:DNA Primers; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D003904:Mitosporic Fungi / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D017931:DNA Primers; D007527:Isoenzymes; D008565:Membrane Proteins; D011753:Pyrones; C412103:trichodion; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011494:Protein Kinases