PURPOSE: Deoxyelephantopin (ESD) and isodeoxyelephantopin (ESI) are two sesquiterpene lactones derived from the medicinal plant Elephantopus scaber Linn. (Asteraceae). Although they are used for the treatment of a wide variety of proinflammatory diseases, very little is known about their mechanism of action. Because most genes that control inflammation are regulated by activation of the transcription factor nuclear factor-kappaB (NF-kappaB), we postulated that ESD and ESI mediate their activities through modulation of the NF-kappaB activation pathway. EXPERIMENTAL DESIGN: We investigated the effect of ESI and ESD on NF-kappaB activation by electrophoretic mobility shift assay and NF-kappaB-regulated gene expression by Western blot analysis. RESULTS: We found that ESI suppressed NF-kappaB activation induced by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1beta, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific, and both inducible and constitutive NF-kappaB activation was blocked. ESI did not interfere with the binding of NF-kappaB to DNA but rather inhibited IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ESI also suppressed the expression of TNF-induced NF-kappaB-regulated, proliferative, antiapoptotic, and metastatic gene products. These effects correlated with enhancement of apoptosis induced by TNF and suppression of TNF-induced invasion and receptor activator of NF-kappaB ligand-induced osteoclastogenesis. CONCLUSION: Our results indicate that ESI inhibits NF-kappaB activation and NF-kappaB-regulated gene expression, which may explain the ability of ESI to enhance apoptosis and inhibit invasion and osteoclastogenesis.
PURPOSE:Deoxyelephantopin (ESD) and isodeoxyelephantopin (ESI) are two sesquiterpene lactones derived from the medicinal plant Elephantopus scaber Linn. (Asteraceae). Although they are used for the treatment of a wide variety of proinflammatory diseases, very little is known about their mechanism of action. Because most genes that control inflammation are regulated by activation of the transcription factor nuclear factor-kappaB (NF-kappaB), we postulated that ESD and ESI mediate their activities through modulation of the NF-kappaB activation pathway. EXPERIMENTAL DESIGN: We investigated the effect of ESI and ESD on NF-kappaB activation by electrophoretic mobility shift assay and NF-kappaB-regulated gene expression by Western blot analysis. RESULTS: We found that ESI suppressed NF-kappaB activation induced by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1beta, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific, and both inducible and constitutive NF-kappaB activation was blocked. ESI did not interfere with the binding of NF-kappaB to DNA but rather inhibited IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ESI also suppressed the expression of TNF-induced NF-kappaB-regulated, proliferative, antiapoptotic, and metastatic gene products. These effects correlated with enhancement of apoptosis induced by TNF and suppression of TNF-induced invasion and receptor activator of NF-kappaB ligand-induced osteoclastogenesis. CONCLUSION: Our results indicate that ESI inhibits NF-kappaB activation and NF-kappaB-regulated gene expression, which may explain the ability of ESI to enhance apoptosis and inhibit invasion and osteoclastogenesis.
Authors: Karin Jöhrer; Marlene Obkircher; Daniel Neureiter; Johanna Parteli; Claudia Zelle-Rieser; Eva Maizner; Johann Kern; Martin Hermann; Frank Hamacher; Olaf Merkel; Nathalie Wacht; Christian Zidorn; Marcel Scheideler; Richard Greil Journal: J Mol Med (Berl) Date: 2011-12-29 Impact factor: 4.599