Mechanism of HMGB1 release inhibition from RAW264.7 cells by oleanolic acid in Prunus mume Sieb. et Zucc.
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)-alpha, 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.
Kawahara
Ko-Ichi
K
Department of Laboratory and Vascular Medicine Cardiovascular and Respiratory Disorders Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan.
Hashiguchi
Teruto
T
Masuda
Kazuo
K
Saniabadi
Abbi R
AR
Kikuchi
Kiyoshi
K
Tancharoen
Salunya
S
Ito
Takashi
T
Miura
Naoki
N
Morimoto
Yoko
Y
Biswas
Kamal K
KK
Nawa
Yuko
Y
Meng
Xiaojie
X
Oyama
Yoko
Y
Takenouchi
Kazunori
K
Shrestha
Binita
B
Sameshima
Hisayo
H
Shimizu
Toshiaki
T
Adachi
Taro
T
Adachi
Masakazu
M
Maruyama
Ikuro
I
D000818:Animals; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D024243:HMGB1 Protein / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009828:Oleanolic Acid / Q000302:isolation & purification / Q000494:pharmacology*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D027861:Prunus / Q000737:chemistry*; D055571:Secretory Pathway / Q000187:drug effects*
D000975:Antioxidants; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D010936:Plant Extracts; D009828:Oleanolic Acid; D051547:Heme Oxygenase-1