Saikosaponin a inhibits LPS-induced inflammatory response by inducing liver X receptor alpha activation in primary mouse macrophages.
The aim of this study was to investigate the effects of SSa on LPS-induced endotoxemia in mice and clarify the possible mechanism. An LPS-induced endotoxemia mouse model was used to confirm the anti-inflammatory activity of SSa in vivo. The primary mouse macrophages were used to investigate the molecular mechanism and targets of SSa in vitro. In vivo, the results showed that SSa improved survival during lethal endotoxemia. In vitro, our results showed that SSa dose-dependently inhibited the expression of TNF-α, IL-6, IL-1β, IFN-β-and RANTES in LPS-stimulated primary mouse macrophages. Western blot analysis showed that SSa suppressed LPS-induced NF-κB and IRF3 activation. Furthermore, SSa disrupted the formation of lipid rafts by depleting cholesterol and inhibited TLR4 translocation into lipid rafts. Moreover, SSa activated LXRα, ABCA1 and ABCG1. Silencing LXRα abrogated the effect of SSa. In conclusion, the anti-inflammatory effects of SSa is associated with activating LXRα dependent cholesterol efflux pathway which result in disrupting lipid rafts by depleting cholesterol and reducing translocation of TLR4 to lipid rafts, thereby attenuating LPS mediated inflammatory response.
Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, People's Republic of China.
Zhengkai
Z
Wei
Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, People's Republic of China.
Jingjing
J
Wang
Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, People's Republic of China.
Mingyu
M
Shi
Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, People's Republic of China.
Weijian
W
Liu
Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, People's Republic of China.
Zhengtao
Z
Yang
Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, People's Republic of China.
Yunhe
Y
Fu
D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism; D005260:Female; D007249:Inflammation; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides; D000071518:Liver X Receptors / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D012503:Saponins / Q000494:pharmacology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D016896:Treatment Outcome
D064286:ATP Binding Cassette Transporter 1; D000893:Anti-Inflammatory Agents; D002784:Cholesterol; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D016328:NF-kappa B; D009828:Oleanolic Acid; D012503:Saponins; D051197:Toll-Like Receptor 4; C577833:Abca1 protein, mouse; C000605214:Nr1h3 protein, mouse; C493487:Tlr4 protein, mouse; C025759:saikosaponin D
IRF3; Immune response; Immunity; Immunology and Microbiology Section; NF-κB; TLR4; lipid raft; saikosaponin a