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Stercurensin inhibits nuclear factor‐κB‐dependent inflammatory signals through attenuation of TAK1–TAB1 complex formation
Author(s) -
Kim YoungJoo,
Kim HanCheon,
Ko Hyeonseok,
Amor Evangeline C.,
Lee Jong Wha,
Yang Hyun Ok
Publication year - 2011
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.22945
Subject(s) - nitric oxide synthase , nitric oxide , microbiology and biotechnology , in vivo , chemistry , tumor necrosis factor alpha , nf κb , electrophoretic mobility shift assay , nfkb1 , lipopolysaccharide , kinase , iκbα , signal transduction , biology , biochemistry , transcription factor , immunology , organic chemistry , gene
We identified a chalcone, 2′,4′‐dihydroxy‐6′‐methoxy‐3′‐methylchalcone (stercurensin), as an active compound isolated from the leaves of Syzygium samarangense . In the present study, the anti‐inflammatory effects and underlying mechanisms of stercurensin were examined using lipopolysaccharide (LPS)‐stimulated RAW264.7 cells and mice. To determine the effects of stercurensin in vitro, inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2) expression were analyzed by RT‐PCR and immunoblotting. Nuclear factor‐κB (NF‐κB) activation and its upstream signaling cascades were also investigated using a dual‐luciferase reporter assay, electrophoretic mobility shift assay, immunoblotting, immunofluorescence, and immunoprecipitation. To verify the effects of stercurensin in vivo, the mRNA expression levels of iNOS and COX‐2 were evaluated in isolated mouse peritoneal macrophages by quantitative real‐time PCR, and the production of tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and IL‐1β were assessed in serum samples from mice using a Luminex system. Pretreatment with stercurensin reduced LPS‐induced iNOS and COX‐2 expression, thereby inhibiting nitric oxide (NO) and prostaglandin E 2 production, respectively. In addition, an inhibitory effect of stercurensin on NF‐κB activation was shown by the recovery of LPS‐induced inhibitor of κB (I‐κB) degradation after blocking the transforming growth factor‐β‐activated kinase 1 (TAK1)/I‐κB kinase signaling pathway. In mouse models, stercurensin negatively regulated NF‐κB‐dependent pro‐inflammatory mediators and cytokines. These results demonstrate that stercurensin modulates NF‐κB‐dependent inflammatory pathways through the attenuation of TAK1–TAB1 complex formation. Our findings demonstrating the anti‐inflammatory effects of stercurensin in vitro and in vivo will aid in understanding the pharmacology and mode of action of stercurensin. J. Cell. Biochem. 112: 548–558, 2011. © 2010 Wiley‐Liss, Inc.