Oxacyclododecindione, a novel inhibitor of IL-4 signaling from Exserohilum rostratum.
In a screening program for new metabolites from fungi inhibiting the IL-4 mediated signal transduction, a novel chlorinated macrocyclic lactone, designated as oxacyclododecindione, was isolated from fermentations of the imperfect fungus Exserohilum rostratum. The structure was determined by a combination of spectroscopic techniques. Oxacyclododecindione inhibits the IL-4 induced expression of the reporter gene secreted alkaline phosphatase (SEAP) in transiently transfected HepG2 cells with IC50 values of 20-25 ng/ml (54-67.5 nM). Studies on the mode of action of the compound revealed that the inhibition of the IL-4 dependent signaling pathway is caused by blocking the binding of the activated STAT6 transcription factors to the DNA binding site without inhibiting tyrosine phosphorylation. The compound has no antibacterial or antifungal activity.
Erkel
Gerhard
G
Department of Biotechnology, University of Kaiserslautern, Kaiserslautern, Germany. erkel@ibwf.de
Belahmer
Hanane
H
Serwe
Annegret
A
Anke
Timm
T
Kunz
Horst
H
Kolshorn
Heinz
H
Liermann
Johannes
J
Opatz
Till
T
D015153:Blotting, Western; D045744:Cell Line, Tumor; D005285:Fermentation; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology*; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D003904:Mitosporic Fungi / Q000737:chemistry* / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014162:Transfection
D047028:Macrocyclic Compounds; D050800:STAT6 Transcription Factor; C532274:oxacyclododecindione; D015847:Interleukin-4