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Identification of plumericin as a potent new inhibitor of the NF ‐ κB pathway with anti‐inflammatory activity in vitro and in vivo
Author(s) -
Fakhrudin N,
Waltenberger B,
Cabaravdic M,
Atanasov A G,
Malainer C,
Schachner D,
Heiss E H,
Liu R,
Noha S M,
Grzywacz A M,
MihalyBison J,
Awad E M,
Schuster D,
Breuss J M,
Rollinger J M,
Bochkov V,
Stuppner H,
Dirsch V M
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12558
Subject(s) - transactivation , iκb kinase , iκbα , nf κb , transfection , phosphorylation , in vivo , microbiology and biotechnology , chemistry , kinase , signal transduction , biology , biochemistry , transcription factor , gene
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 H imatanthus sucuuba , an A mazonian plant traditionally used to treat inflammation‐related disorders. Experimental Approach 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. Key Results Plumericin inhibited NF ‐ κB ‐mediated transactivation of a luciferase reporter gene ( IC 50 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.