1‐Dehydro‐[10]‐gingerdione from ginger inhibits IKKβ activity for NF‐κB activation and suppresses NF‐κB‐regulated expression of inflammatory genes

Abstract

BACKGROUND AND PURPOSEPungent 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-kB-regulated expression of inflammatory genes linked to toll-like receptor (TLR)-mediated innate immunity. EXPERIMENTAL APPROACHRAW 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 kB (IkB) kinase b (IKKb) 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 RESULTSD10G directly inhibited the catalytic activity of cell-free IKKb. Moreover, D10G irreversibly inhibited cytoplasmic IKKb-catalysed IkBa phosphorylation in macrophages activated by TLR agonists or TNF-a, and also IKKb vector-elicited NF-kB transcriptional activity in these cells. These effects of D10G were abolished by substitution of the Cys 179 with Ala in the activation loop of IKKb, indicating a direct interacting site of D10G. This mechanism was shown to mediate D10G-induced disruption of NF-kB activation in LPS-stimulated macrophages and the suppression of NF-kB-regulated gene expression of inducible NOS, COX-2 and IL-6. CONCLUSION AND IMPLICATIONSThis study demonstrates that IKKb is a molecular target of D10G involved in the suppression of NF-kB-regulated gene expression in LPS-activated macrophages; this suggests D10G has therapeutic potential in NF-kB-associated inflammation and autoimmune disorders. AbbreviationsAP-1, activating protein 1; D10G, 1-dehydro-[10]-gingerdione; IkB, inhibitory kB; IKKb, IkB kinase b; iNOS, inducible NOS; PTN, parthenolide; TNFSF11, receptor activator of NF-kB ligand; SEAP, secretory alkaline phosphatase; TLR, toll-like receptor

Dietary Influence on Pain via the Immune System

“…123 This latter effect on inflammatory cytokine activity may also be due to the discovery that ginger directly activates IKKβ, leading to reduced IkB phosphorylation in human macrophages treated with LPS. 124 . In whole animals, this effect was confirmed when mice given LPS showed reduced levels of IFN-γ and IL-6 in serum and reduced NFκB and COX2 expression with ginger treatment.…”

The Effect of Alcoholic Extract of Ginger on Apoptosis and Inflammation of Germ Cells in Streptozotocin-Induced Diabetic Rats

“…Another study revealed that ginger suppresses expression of inflammatory genes in a NF-κB dependent manner [26]. NF-κB is a main transcription factor down-stream of TLR2 and 4 and participates in the expression of the TLRs [27][28][29].…”

Efeito anti-inflamatório do gengibre e possível via de sinalização

“…Os TLRs quando ativados, transmitem cascatas de sinais que culminam na fosforilação do IkBα catalisado por IKKB, dando origem ao fator de transcrição kappa B (NF-kB), um potente indutor da transcrição de genes de citocinas pró-inflamatórias (RULAND; MAK, 2003). Lee et al (2012) demonstraram que IKKB é alvo molecular do composto 1-Dehydro-[10]-gingerdione (D10G), bloqueando sua ação catalítica e consequentemente suprimindo a expressão de NF-KB.…”