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INFLAMMATION AND IMMUNOPHARMACOLOGY

Blockade of Nuclear Factor-B Signaling Pathway and Anti-Inflammatory Activity of Cardamomin, a Chalcone Analog from Alpinia conchigera

Anticancer Research Laboratory (J.-H.L., H.S.J., X.J., D.L., Y.-S.H., K.L., J.J.L.) and Laboratory of Immune Modulator (S.L.), Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea; and Faculty of Chemistry, Vietnam National University, Hanoi, Vietnam (P.M.G., P.T.S.)

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 (IB) but also activation of inhibitor B (IB) kinases and nuclear translocation of NF-B. Further analyses revealed that cardamomin did not directly inhibit IB 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 NH₂-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.

Address correspondence to: Dr. Jung Joon Lee, Anticancer Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, P.O. Box 115, Yuseong, Daejeon 305-600, Korea. E-mail: jjlee{at}kribb.re.kr

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