Identification of plumericin as a potent new inhibitor of the NF ‐ κB pathway with anti‐inflammatory activity in vitro and in vivo

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.