3,4,5-trihydroxycinnamic acid inhibits lipopolysaccharide (LPS)-induced inflammation by Nrf2 activation in vitro and improves survival of mice in LPS-induced endotoxemia model in vivo.
NF-E2-related factor 2 (Nrf2) has been demonstrated to be a key transcription factor regulating the anti-inflammatory genes including heme oxygenase-1 (HO-1) in experimental sepsis models. Based on the fact that 3,4,5-trihydorxycinnamic acid (THC) has been reported to possess anti-inflammatory properties in BV2 microglial cells, the possible effects of THC and its underlying mechanism was examined against lipopolysaccharide (LPS)-induced RAW 264.7 cell culture and septic mouse models. Pretreatment of RAW 264.7 cells with THC significantly attenuated LPS-induced NO, PGE2 production, and expression of iNOS and COX-2. THC also significantly suppressed LPS-induced release of pro-inflammatory cytokines and degradation of IκB-α. Increased phosphorylation of Nrf2 and nuclear translocation of Nrf2 were observed with THC treatment with consequent expression of HO-1. The data demonstrated that multiple signaling pathways including Akt, p38, and PKC are involved in the THC-induced activation of Nrf2/HO-1 pathway. Treatment of THC resulted in significantly increased survival of LPS-induced septic mice. THC also significantly ameliorated LPS-induced septic features such as hypothermia and increased vascular leakage. In accordance with the data from cell culture model, THC exhibited increased expression of HO-1 in kidney and decreased serum level of pro-inflammatory mediators such as TNF-α, IL-1β, and NO. Taken together, the present study for the first time demonstrates that THC inhibits inflammation in LPS-induced RAW264.7 cells by Nrf2 activation and improves survival of mice in LPS-induced endotoxemia model.
Department of Pharmacology, College of Medicine, Kangwon National University, Hyoja-2, Chuncheon, 200-701, Kangwon, South Korea.
Jae-Won
JW
Lee
Chang Jun
CJ
Bae
Yong-Jun
YJ
Choi
Song-In
SI
Kim
Yong-Soo
YS
Kwon
Hee Jae
HJ
Lee
Sung-Soo
SS
Kim
Wanjoo
W
Chun
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005707:Gallic Acid / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D005707:Gallic Acid