title: 1-Dehydro-[10]-gingerdione from ginger inhibits IKKβ activity for NF-κB activation and suppresses NF-κB-regulated expression of inflammatory genes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, Korea.
authors.forename: Hwa Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Sun Hong
authors.initials: SH
authors.lastname: Park
authors.forename: Misoon
authors.initials: M
authors.lastname: Lee
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Shi Yong
authors.initials: SY
authors.lastname: Ryu
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.forename: Bang Yeon
authors.initials: BY
authors.lastname: Hwang
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D020939:Zingiber officinale; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C561631:(10)-dehydrogingerdione; D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D009569:Nitric Oxide; D006139:Guaiacol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D000469:Alkaline Phosphatase