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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 316; no. 1; pp. 271 - 278
• Main Authors: Lee, Jeong-Hyung, Jung, Haeng Sun, Giang, Phan Minh, Jin, Xuejun, Lee, Sangku, Son, Phan Tong, Lee, Dongho, Hong, Young-Soo, Lee, Kyeong, Lee, Jung Joon
• Format: Journal Article
• Language: English
• Published: United States 01.01.2006
• Subjects: Alpinia - chemistry; Animals; Anti-Inflammatory Agents; Blotting, Western; Cell Survival - drug effects; Chalcones - pharmacology; Cyclooxygenase 2 Inhibitors - pharmacology; Electrophoretic Mobility Shift Assay; Enzyme Inhibitors - pharmacology; Humans; I-kappa B Proteins - drug effects; Lipopolysaccharides - pharmacology; Luciferases - genetics; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Inbred C57BL; NF-kappa B - antagonists & inhibitors; Nitric Oxide Synthase Type II - antagonists & inhibitors; Oncogene Protein p65(gag-jun) - drug effects; Oncogene Protein p65(gag-jun) - metabolism; Phosphorylation; Plasmids - genetics; Signal Transduction - drug effects; Transcriptional Activation - drug effects; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-3565

Nuclear factor-kappaB (NF-kappaB) and the signaling pathways that regulate its activity have become a focal point for intense drug discovery and development efforts. NF-kappaB regulates the transcription of a large number of genes, particularly those involved in immune, inflammatory, and antiapoptotic responses. In our search for NF-kappaB inhibitors from natural resources, we identified cardamomin, 2',4'-dihydroxy-6'-methoxychalcone, as an inhibitor of NF-kappaB activation from Alpinia conchigera Griff (Zingiberaceae). In present study, we demonstrated the effect of cardamomin on NF-kappaB activation in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and LPS-induced mortality. This compound significantly inhibited the induced expression of NF-kappaB reporter gene by LPS or tumor necrosis factor (TNF)-alpha in a dose-dependent manner. LPS-induced production of TNF-alpha 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 kappaBalpha (IkappaBalpha) but also activation of inhibitor kappaB (IkappaB) kinases and nuclear translocation of NF-kappaB. Further analyses revealed that cardamomin did not directly inhibit IkappaB 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-kappaB. 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-alpha. Together, cardamomin could be valuable candidate for the intervention of NF-kappaB-dependent pathological condition such as inflammation.