Mechanism of HMGB1 release inhibition from RAW264.7 cells by oleanolic acid in Prunus mume Sieb. et Zucc.

Abstract

Abstract. High mobility group box-1 protein (HMGB1), primarily from the nucleus, is released into the extracellular milieu either passively from necrotic cells or actively through secretion by monocytes/macrophages. Extracellular HMGB1 acts as a potent inflammatory agent by promoting the release of cytokines such as tumor necrosis factor (TNF)-·, has procoagulant activity, and is involved in death due to sepsis. Accordingly, HMGB1 is an appropriate therapeutic target. In this study, we found that an extract of Prunus mume Sieb. et Zucc. (Ume) fruit (Ume extract), an abundant source of triterpenoids, strongly inhibited HMGB1 release from lipopolysaccharide (LPS)-stimulated macrophage-like RAW264.7 cells. The inhibitory effect on HMGB1 release was enhanced by authentic oleanolic acid (OA), a naturally occurring triterpenoid. Similarly, the HMGB1 release inhibitor in Ume extract was found to be OA. Regarding the mechanisms of the inhibition of HMGB1 release, the OA or Ume extract was found to activate the transcription factor Nrf2, which binds to the antioxidative responsive element, and subsequently the heme oxygenase (HO)-1 protein was induced, indicating that the inhibition of HMGB1 release from LPS-stimulated RAW264.7 cells was mediated via the Nrf2/HO-1 system; an essentially antioxidant effect. These results suggested that natural sources of triterpenoids warrant further evaluation as 'rescue' therapeutics for sepsis and other potentially fatal systemic inflammatory disorders.

Alleviation of Hepatic Ischemia Reperfusion Injury by Oleanolic Acid Pretreating via Reducing HMGB1 Release and Inhibiting Apoptosis and Autophagy

“…These findings suggest that HMGB1 is a potential target for the treatment of hepatic IRI. OA inhibits HMGB1-mediated pathway activation in lipopolysaccharide-stimulated RAW264.7 cells [32] and human umbilical vein endothelial cells [33]. HMGB1 acts as a late mediator of the inflammatory response, activating monocytes to secrete proinflammatory cytokines, including TNF- α and IL-1 [34], and inducing inflammation as the ligand of TLR4 [18].…”

Comprehensive Review of Phytochemical Constituents, Pharmacological Properties, and Clinical Applications of Prunus mume

“…Extracellular high-mobility group box-1 protein (HMGB1) is a potent inflammatory agent that can promote the release of pro-inflammatory mediators such as TNF-α. The triterpenoid compounds extracted from P. mume, such as oleanolic acid (compound 133), inhibited HMGB1 release from lipopolysaccharide (LPS)-stimulated RAW246.7 cells via the Nrf2/HO-1 pathway (Kawahara et al, 2009). MK615 or a water extract of P. mume inhibited the production of cytokines induced by LPS in RAW246.7 cells and in gingival fibroblast cells.…”