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

FEBS Lett. 2000 Jul 21;477(3):219-23. doi: 10.1016/s0014-5793(00)01784-1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cyclooxygenase 2
  • DNA Primers
  • HeLa Cells
  • Humans
  • Isoenzymes / metabolism
  • Macrophages / drug effects
  • Macrophages / enzymology
  • Macrophages / metabolism
  • Membrane Proteins
  • Mice
  • Mitosporic Fungi / metabolism*
  • Nitric Oxide Synthase / metabolism
  • Phosphorylation
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Protein Kinases / metabolism
  • Pyrones / pharmacology*
  • Signal Transduction / drug effects*

Substances

  • DNA Primers
  • Isoenzymes
  • Membrane Proteins
  • Pyrones
  • trichodion
  • Nitric Oxide Synthase
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Protein Kinases