Premium
1‐Dehydro‐[10]‐gingerdione from ginger inhibits IKKβ activity for NF‐κB activation and suppresses NF‐κB‐regulated expression of inflammatory genes
Author(s) -
Lee Hwa Young,
Park Sun Hong,
Lee Misoon,
Kim HyeJin,
Ryu Shi Yong,
Kim Nam Doo,
Hwang Bang Yeon,
Hong Jin Tae,
Han SangBae,
Kim Youngsoo
Publication year - 2012
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/j.1476-5381.2012.01980.x
Subject(s) - iκb kinase , nf κb , tlr4 , iκbα , signal transduction , innate immune system , microbiology and biotechnology , nfkb1 , kinase , chemistry , proinflammatory cytokine , phosphorylation , gene expression , biology , receptor , biochemistry , inflammation , transcription factor , gene , immunology
BACKGROUND AND PURPOSE Pungent constituents of ginger ( Zingiber officinale ) have beneficial effects on inflammatory pain and arthritic swelling. However, the molecular basis for these pharmacological properties is only partially understood. Here, we investigated the molecular target of 1‐dehydro‐[10]‐gingerdione (D10G), one of the pungent constituents of ginger, that mediates its suppression of NF‐κB‐regulated expression of inflammatory genes linked to toll‐like receptor (TLR)‐mediated innate immunity. EXPERIMENTAL APPROACH RAW 264.7 macrophages or primary macrophages‐derived from bone marrows of C57BL/6 or C3H/HeJ mice were stimulated with the TLR4 agonist LPS in the presence of D10G. Catalytic activity of inhibitory κB (IκB) kinase β (IKKβ) was determined by a kinase assay and immunoblot analysis, and the expression of inflammatory genes by RT‐PCR analysis and a promoter‐dependent reporter assay. KEY RESULTS D10G directly inhibited the catalytic activity of cell‐free IKKβ. Moreover, D10G irreversibly inhibited cytoplasmic IKKβ‐catalysed IκBα phosphorylation in macrophages activated by TLR agonists or TNF‐α, and also IKKβ vector‐elicited NF‐κB transcriptional activity in these cells. These effects of D10G were abolished by substitution of the Cys 179 with Ala in the activation loop of IKKβ, indicating a direct interacting site of D10G. This mechanism was shown to mediate D10G‐induced disruption of NF‐κB activation in LPS‐stimulated macrophages and the suppression of NF‐κB‐regulated gene expression of inducible NOS, COX‐2 and IL‐6. CONCLUSION AND IMPLICATIONS This study demonstrates that IKKβ is a molecular target of D10G involved in the suppression of NF‐κB‐regulated gene expression in LPS‐activated macrophages; this suggests D10G has therapeutic potential in NF‐κB‐associated inflammation and autoimmune disorders.