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KMID : 0043320180410030314
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Archives of Pharmacal Research
2018 Volume.41 No. 3 p.314 ~ p.323
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Dihydropyranoaurone compound damaurone D inhibits LPS-induced inflammation and liver injury by inhibiting NF-κB and MAPK signaling independent of AMPK
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Wang Zheng
Ka Sun-O
Han Young-Taek
Bae Eun-Ju
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Abstract
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Recently, we reported the synthesis of damaurone D (DD), originally derived from Rosa damascene, and its anti-inflammatory effect in macrophages. Here, we investigated the molecular mechanism underlying the anti-inflammatory effect of DD in macrophages and further tested whether DD is protective against lipopolysaccharide (LPS)-induced liver injury. DD inhibited LPS-stimulated expression of pro-inflammatory genes and cytokine/chemokine secretion in a concentration-dependent manner in RAW 264.7 cells and thioglycolate-elicited mouse peritoneal macrophages. DD suppressed LPS-stimulated nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, as demonstrated by reduction in IκB kinase α/β phosphorylation, IκBα degradation, and levels of phosphorylated ERK, JNK, and p38 MAPK. The luciferase reporter activity of NF-κB and activator protein 1 was also attenuated by DD pretreatment. Furthermore, DD treatment induced AMP-activated protein kinase (AMPK) activation in cells and mouse liver, although the anti-inflammatory effect of DD was similar in dominant-negative AMPK-overexpressing cells. Lastly, DD-treated mice were protected against LPS-induced acute liver injury, based on morphologic and immunohistochemical observations; reduction in the plasma levels of aspartate aminotransferase, TNF-α, and MCP-1; and a decrease in inflammatory gene expression. In summary, our findings indicate that DD can protect against LPS-stimulated inflammation and liver injury at least partly by suppression of NF-κB and MAPK signaling pathways.
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KEYWORD
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Macrophages, Anti-inflammation, LPS, Liver injury, NF-κB, MAPKs
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