Abstract
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.
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Cohn L, Elias JA, Chupp GL . Asthma: Mechanisms of disease persistence and progression. Annu Rev Immunol 22: 789–815 ( 2004)
Nakajima H, Takatsu K . Role of cytokines in allergic airway inflammation. Int Arch Allergy Immunol 142: 265–273 ( 2007)
Pernis AB, Rothman PB . JAK-STAT signaling in asthma. J Clin Invest 109: 1279–1283 ( 2002)
Hebenstreit D, Wirnsberger G, Horjes-Hoeck J, Duschl A . Signaling mechanisms, interaction partners, and target genes of STAT6. Cytokine Growth Factor Rev 17: 173–188 ( 2006)
Colgan J, Rothman P . Manipulation of signaling to control allergic inflammation. Curr Opin Allergy Clin Immunol 7: 51–56 ( 2007)
White TJ, Bruns T, Lee S, Taylor J . Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics. In: Innis MA, Gelfand DH, Sninsky JJ, White TJ (eds). PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, pp. 315–322 ( 1990)
Rether J, Erkel G, Sterner O, Anke T . Inhibition of TNF-α promoter activity and synthesis by A11-99-1, a new cyclopentenone from the ascomycete Mollisia melaleuca. Z Naturforsch 60c: 478–484 ( 2005)
Mikita T, Campbell D, Wu P, Williamson K, Schindler U . Requirements for interleukin-4-induced gene expression and functional characterization of STAT6. Mol Cell Biol 16: 5811–5820 ( 1996)
Weidler M, Rether J, Anke T, Erkel G . Inhibition of interleukin-6 signaling by galiellalactone. FEBS Lett 484: 1–6 ( 2000)
Erkel G, Anke T, Sterner O . Inhibition of NF-κB activation by panepoxydone. Biochem Biophys Res Commun 226: 214–221 ( 1996)
Elzner S . (S)-(−)-Curvularin als Leitstruktur für die Synthese neuartiger antiinflammatorischer Wirkstoffe. Dissertation, Universität Mainz ( 2005)
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Erkel, G., Belahmer, H., Serwe, A. et al. Oxacyclododecindione, a Novel Inhibitor of IL-4 Signaling from Exserohilum rostratum. J Antibiot 61, 285–290 (2008). https://doi.org/10.1038/ja.2008.40
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DOI: https://doi.org/10.1038/ja.2008.40
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