Dihydroquercetin (DHQ) ameliorated concanavalin A-induced mouse experimental fulminant hepatitis and enhanced HO-1 expression through MAPK/Nrf2 antioxidant pathway in RAW cells.
Autoimmune hepatitis represents a ubiquitous human health problem and has a poor prognosis. Dihydroquercetin (DHQ), a well-known antioxidant, significantly inhibits fulminant hepatitis through anti-oxidant and anti-inflammation mechanisms. In this study, we show that administration of DHQ ameliorated concanavalin A (ConA)-induced mouse liver injury by increasing the survival rate, reducing the serum ALT and AST level, preventing histopathological injuries and decreasing pro-inflammatory cytokine mRNA expression in hepatic tissue. As macrophages/Kupffer cells in oxidative stress and pro-inflammatory mediators play an important role in the pathogenesis of immune-mediated hepatitis, we further exposed mouse RAW264 macrophage cell lines to ConA in vitro and found that DHQ significantly inhibited mRNA expression and secretion of IFN-γ and TNF-α in cell culture supernatant. In addition, DHQ significantly enhanced heme oxygenase-1 (HO-1) expression in a dose- and time-dependent manner via increased Nrf2 expression in cytoplasm and nuclear translocation. Furthermore, DHQ enhanced phosphorylation of three members of the mitogen-activated protein kinase (MAPK) family, and cell treatment with MEK/ERK (PD98059), p38 (SB203580) and JNK (SP600125) inhibitors reduced DHQ-induced HO-1 expression. These results indicate that DHQ possesses hepatoprotective properties against ConA-induced liver injury, which are attributed to its ability to scavenge oxidative stress and to inhibit the release of inflammatory mediators via upregulation of HO-1 activity through the MAPK/Nrf2 signaling pathway in macrophages/Kupffer cells.
Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China.
Mingyi
M
Zhao
Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Gastroenterology, Huashan Hospital, Fudan University, Shanghai, China.
Jiajie
J
Chen
Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Ping
P
Zhu
Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Masayuki
M
Fujino
Third Department of Internal Medicine, University of Toyama, Toyama, Japan.
Terumi
T
Takahara
Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
Sumika
S
Toyama
Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Research Institute for Nutrition and Aging, Tokyo, Japan.
Amy
A
Tomita
Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China.
Lingling
L
Zhao
Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China.
Zuocheng
Z
Yang
Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China.
Mingyan
M
Hei
Department of Gastroenterology, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: zhongniping@163.com.
Liang
L
Zhong
Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Jian
J
Zhuang
Research Institute for Nutrition and Aging, Tokyo, Japan.
Shuichi
S
Kimura
Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan. Electronic address: ri-k@ncchd.go.jp.
Xiao-Kang
XK
Li
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D001327:Autoimmune Diseases / Q000188:drug therapy*; D002460:Cell Line; D003208:Concanavalin A / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006505:Hepatitis / Q000188:drug therapy*; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011794:Quercetin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007371:Interferon-gamma; D011794:Quercetin; C003377:taxifolin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases
Antioxidant; ConA; DHQ; HO-1; Hepatitis; Mitogen-activated protein kinases; Nrf2