These authors contributed equally to this work.
Identification of plumericin as a potent new inhibitor of the NF-κB pathway with anti-inflammatory activity in vitro and in vivo
Version of Record online: 18 MAR 2014
© 2013 The Authors. British Journal of Pharmacology published by John Wiley &. Sons Ltd on behalf of The British Pharmacological Society.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
British Journal of Pharmacology
Volume 171, Issue 7, pages 1676–1686, April 2014
How to Cite
Fakhrudin, N., Waltenberger, B., Cabaravdic, M., Atanasov, A. G., Malainer, C., Schachner, D., Heiss, E. H., Liu, R., Noha, S. M., Grzywacz, A. M., Mihaly-Bison, J., Awad, E. M., Schuster, D., Breuss, J. M., Rollinger, J. M., Bochkov, V., Stuppner, H. and Dirsch, V. M. (2014), Identification of plumericin as a potent new inhibitor of the NF-κB pathway with anti-inflammatory activity in vitro and in vivo. British Journal of Pharmacology, 171: 1676–1686. doi: 10.1111/bph.12558
- Issue online: 18 MAR 2014
- Version of Record online: 18 MAR 2014
- Accepted manuscript online: 16 DEC 2013 05:54AM EST
- Manuscript Accepted: 9 DEC 2013
- Manuscript Revised: 28 NOV 2013
- Manuscript Received: 2 AUG 2013
- Austrian Federal Ministry for Science and Research. Grant Numbers: ACM-2007-00178, ACM-2008-00857, ACM-2009-01206
- Austrian Science Fund (FWF). Grant Numbers: NFN-S10704, S10711, S10703, S10709/10713
- natural products;
- adhesion molecules
Background and Purpose
The transcription factor NF-κB orchestrates many pro-inflammatory signals and its inhibition is considered a promising strategy to combat inflammation. Here we report the characterization of the natural product plumericin as a highly potent inhibitor of the NF-κB pathway with a novel chemical scaffold, which was isolated via a bioactivity-guided approach, from extracts of Himatanthus sucuuba, an Amazonian plant traditionally used to treat inflammation-related disorders.
A NF-κB luciferase reporter gene assay was used to identify NF-κB pathway inhibitors from H. sucuuba extracts. Monitoring of TNF-α-induced expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin by flow cytometry was used to confirm NF-κB inhibition in endothelial cells, and thioglycollate-induced peritonitis in mice to confirm effects in vivo. Western blotting and transfection experiments were used to investigate the mechanism of action of plumericin.
Plumericin inhibited NF-κB-mediated transactivation of a luciferase reporter gene (IC50 1 μM), abolished TNF-α-induced expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin in endothelial cells and suppressed thioglycollate-induced peritonitis in mice. Plumericin exerted its NF-κB pathway inhibitory effect by blocking IκB phosphorylation and degradation. Plumericin also inhibited NF-κB activation induced by transfection with the constitutively active catalytic subunit of the IκB kinase (IKK-β), suggesting IKK involvement in the inhibitory action of this natural product.
Conclusion and Implications
Plumericin is a potent inhibitor of NF-κB pathways with a new chemical scaffold. It could be further explored as a novel anti-inflammatory lead compound.