Inhibition of interleukin-6 signaling by galiellalactone.
A search for inhibitors of the IL-6-mediated signal transduction in HepG2 cells using secreted alkaline phosphatase (SEAP) as reporter gene resulted in the isolation of galiellalactone (1) from fermentations of the ascomycete strain A111-95. Galiellalactone inhibits the IL-6-induced SEAP expression with IC(50) values of 250-500 nM by blocking the binding of the activated Stat3 dimers to their DNA binding sites without inhibiting the tyrosine and serine phosphorylation of the Stat3 transcription factor. Due to its selective activity, galiellalactone may serve as a lead compound for the development of new therapeutic agents for diseases originating from the inappropriate expression of IL-6 and as molecular tool to dissect the JAK/STAT pathways.
Weidler
M
M
Institut für Biotechnologie und Wirkstoff-Forschung, Kaiserslautern, Germany.
Rether
J
J
Anke
T
T
Erkel
G
G
D000210:Acute-Phase Reaction; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D001203:Ascomycota / Q000737:chemistry*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006367:HeLa Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D015850:Interleukin-6 / Q000494:pharmacology; D019169:Jurkat Cells; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors
D000469:Alkaline Phosphatase; D004247:DNA; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D007783:Lactones; D020928:Mitogen-Activated Protein Kinases; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C416043:galiellalactone