Decursin inhibits induction of inflammatory mediators by blocking nuclear factor-kappaB activation in macrophages.
In the course of screening inhibitors of matrix metalloproteinase (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 by LPS in a dose-dependent manner at concentrations below 60 microM with no sign of cytotoxicity. The suppressive effect of decursin was observed not only in cells stimulated with ligands for TLR4, TLR2, TLR3, and TLR9 but also in cells stimulated with interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha, 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-1beta, and TNF-alpha) secretion induced by LPS. 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 IkappaB and nuclear translocation of NF-kappaB in THP-1 cells activated with LPS. Furthermore, expression of a luciferase reporter gene under the promoter containing NF-kappaB binding sites was blocked by decursin. These data indicate that decursin is a novel inhibitor of NF-kappaB activation in signaling induced by TLR ligands and cytokines.
Kim
Jung-Hee
JH
Department of Genetic Engineering, College of Natural Sciences, Kyungpook National University, Taegu 702-701, Korea.
Jeong
Ji-Hye
JH
Jeon
Sung-Tak
ST
Kim
Ho
H
Ock
Jiyeon
J
Suk
Kyoungho
K
Kim
Sang-In
SI
Song
Kyung-Sik
KS
Lee
Won-Ha
WH
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000032:analysis / Q000494:pharmacology*; D001578:Benzopyrans / Q000032:analysis / Q000494:pharmacology*; D002087:Butyrates / Q000032:analysis / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors*; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051193:Toll-Like Receptors / Q000819:agonists
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D002087:Butyrates; D016207:Cytokines; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D010936:Plant Extracts; D051193:Toll-Like Receptors; C101278:decursin; D011493:Protein Kinase C