Received for publication November 23, 2005.
Revised March 1, 2006.
Accepted for publication March 1, 2006.

Decursin inhibits induction of inflammatory mediators by blocking NF-B activation in macrophages

Abstract

In the course of screening inhibitors of MMP-9 induction in macrophages, we isolated decursin, a coumarin compound, from the roots of Angelicae gigas. As a marker for the screening and isolation, we tested expression of MMP-9 in RAW264.7 cells and THP-1 cells after treatment with bacterial lipopolysaccharide (LPS), the TLR-4 ligand. Decursin suppressed MMP-9 expression in cells stimulated LPS in a dose dependent manner at concentrations below 60 µM without any sign of cytotoxicity. The suppressive effect of decursin was also observed not only in cells stimulated with ligands for TLR4, TLR2, TLR3, and TLR9 but also in cells stimulated with interleukin (IL)-1 and tumor necrosis factor (TNF)- indicating that the molecular target of decursin is common signaling molecules induced by these stimulants. In addition to the suppression of MMP-9 expression, decursin blocked nitric oxide production and cytokine (IL-8, MCP-1, IL-1& [beta] and TNF-) secretion induced by LPS. In order to find out the molecular mechanism responsible for the suppressive effect of decursin, we analyzed signaling molecules involved in the TLR-mediated activation of MMP-9 and cytokines. Decursin blocked phosphorylation of IB and nuclear translocation of NF-B in THP-1 cells activated with LPS. Furthermore, expression of a luciferase reporter gene under the promoter containing NF-B binding sites was blocked by decursin. These data indicate that decursin is a novel inhibitor of NF-B activation in signaling induced by TLR ligands and cytokines.

Key words: Tumor necrosis factor, NFkappaB, Leukocytes/Mast cells