Blockade of nuclear factor-?B signaling pathway and anti-inflammatory activity of cardamomin, a chalcone analog from Alpinia conchigera

Abstract

Nuclear factor-?B (NF-?B) and the signaling pathways that regulate its activity have become a focal point for intense drug discovery and development efforts. NF-?B regulates the transcription of a large number of genes, particularly those involved in immune, inflammatory, and antiapoptotic responses. In our search for NF-?B inhibitors from natural resources, we identified cardamomin, 2?,4?-dihydroxy-6?- methoxychalcone, as an inhibitor of NF-?B activation from Alpinia conchigera Griff (Zingiberaceae). In present study, we demonstrated the effect of cardamomin on NF-?B activation in lipopolysaccharide (LPS)- stimulated RAW264.7 cells and LPS-induced mortality. This compound significantly inhibited the induced expression of NF-?B reporter gene by LPS or tumor necrosis factor (TNF)-? in a dose-dependent manner. LPS-induced production of TNF-? and NO as well as expression of inducible nitric-oxide synthase and cyclooxygenase-2 was significantly suppressed by the treatment of cardamomin in RAW264.7 cells. Also, cardamomin inhibited not only LPS-induced degradation and phosphorylation of inhibitor ?B? (I?B?) but also activation of inhibitor ?B (I?B) kinases and nuclear translocation of NF-?B. Further analyses revealed that cardamomin did not directly inhibit I?B kinases, but it significantly suppressed LPS-induced activation of Akt. Moreover, cardamomin suppressed transcriptional activity and phosphorylation of Ser536 of RelA/p65 subunit of NF-?B. However, this compound did not inhibit LPS-induced activation of extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun NH 2-terminal kinase, but significantly impaired activation of p38 mitogen-activated protein kinase. We also demonstrated that pretreatment of cardamomin rescued C57BL/6 mice from LPS-induced mortality in conjunction with decreased serum level of TNF-?. Together, cardamomin could be valuable candidate for the intervention of NF-?B-dependent pathological condition such as inflammation. Copyright ?? 2006 by The American Society for Pharmacology and Experimental Therapeutics.