Received for publication July 14, 2005.
Revised September 16, 2005.
Accepted for publication September 21, 2005.

Blockade of NF-B signaling pathway and anti-inflammatory activity of cardamomin, a chalcone analogue from Alpinia conchigera

Abstract

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. In present study, we demonstrated the effect of cardamomin on NF-B activation in LPS-stimulated RAW264.7 cells and LPS-induced mortality. This compound significantly inhibited the induced expression of NF-B reporter gene by LPS or TNF- in a dose-dependent manner. LPS-induced production of TNF- and NO as well as expression of iNOS and COX-2 was significantly suppressed by the treatment of cardamomin in RAW264.7 cells. Also, cardamomin inhibited not only LPS-induced degradation and phosphorylation of IB, but also activation of IB kinases and nuclear translocation of NF-B. Further analyses revealed that cardamomin did not directly inhibit IB kinases, but 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 ERK and SAPK/JNK, but significantly impaired activation of p38 MAP kinase. We also demonstrated that pretreatment of cardamomin rescued C57BL/6 mice from LPS-induced mortality in conjunction with decreased serum level of TNF-. Taken together, cardamomin could be valuable candidate for the intervention of NF-B-dependent pathological condition such as inflammation.

Key words: Akt, cardamomin, chalcone, inflammation, nuclear factor kappa B, transactivation

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