Inhibition of inducible tumor necrosis factor-α expression by the fungal epipolythiodiketopiperazine gliovirin

Jan Rether 1 , 1 , Annegret Serwe 2 , 2 , Timm Anke 3 , 3  and Gerhard Erkel 4 , 4
  • 1 Institut für Biotechnologie und Wirkstoff-Forschung e.V., Erwin-Schrödinger-Str. 56, D-67663 Kaiserslautern, Germany
  • 2 Department of Biotechnology, University of Kaiserslautern, Paul-Ehrlich-Str. 23, D-67663 Kaiserslautern, Germany
  • 3 Department of Biotechnology, University of Kaiserslautern, Paul-Ehrlich-Str. 23, D-67663 Kaiserslautern, Germany
  • 4 Department of Biotechnology, University of Kaiserslautern, Paul-Ehrlich-Str. 23, D-67663 Kaiserslautern, Germany

Abstract

TNF-α 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-α promoter activity and expression, cultures of the imperfect fungus Trichoderma harzianum were found to produce gliovirin, a previously isolated epipolythiodiketopiperazine. Gliovirin inhibited inducible TNF-α promoter activity and synthesis in LPS/IFN-γ-stimulated macrophages/monocytes and Jurkat T-cells, co-stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA)/ionomycin, in a dose-dependent manner, with IC50 values ranging from 0.21 to 2.1 μM (0.1–1 μg/ml). Studies on the mode of action revealed that gliovirin suppresses TNF-α 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-κB, 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.

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