Inhibition of inducible tumor necrosis factor-alpha expression by the fungal epipolythiodiketopiperazine gliovirin.
TNF-alpha is a major pro-inflammatory cytokine that regulates further cytokine induction, especially of IL-1 and IL-6, in many human diseases including cancer, inflammation and immune disorders. In a search for new inhibitors of inducible TNF-alpha promoter activity and expression, cultures of the imperfect fungus Trichoderma harzianum were found to produce gliovirin, a previously isolated epipolythiodiketopiperazine. Gliovirin inhibited inducible TNF-alpha promoter activity and synthesis in LPS/IFN-gamma-stimulated macrophages/monocytes and Jurkat T-cells, co-stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA)/ionomycin, in a dose-dependent manner, with IC(50) values ranging from 0.21 to 2.1 microM (0.1-1 microg/ml). Studies on the mode of action revealed that gliovirin suppresses TNF-alpha synthesis by inhibiting the activation of extracellular signal-regulated kinase (ERK), thereby blocking the pathway leading to activation of the transcription factors AP-1 and NF-kappaB, the latter of which is involved in the inducible expression of many pro-inflammatory genes. Gliovirin also significantly reduced TPA/ionomycin-induced IL-2 mRNA levels and synthesis in Jurkat cells at low micromolar concentrations.
Rether
Jan
J
Institut für Biotechnologie und Wirkstoff-Forschung e.V., Erwin-Schrödinger-Str. 56, D-67663 Kaiserslautern, Germany.
Serwe
Annegret
A
Anke
Timm
T
Erkel
Gerhard
G
D051546:Cyclooxygenase 2 / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D019169:Jurkat Cells; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020298:U937 Cells
D052246:Cyclooxygenase 2 Inhibitors; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D010879:Piperazines; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C036710:gliovirin; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases