Tetrandrine protects mice from concanavalin A-induced hepatitis through inhibiting NF-kappaB activation.
Tetrandrine (TET) is the major pharmacologically active compound of Chinese herb Stephania tetrandra S Moore, which has been used traditionally for the treatment of rheumatic disorders, silicosis and hypertension. Concanavalin A (ConA)-induced hepatitis (CIH) is a T-cell-dependent hepatitis and a well-established animal model for studying the mechanisms and therapy of immune-mediated hepatotoxicity. The aim of this study was to investigate whether TET could protect mice from CIH. C57BL/6 mice were injected with ConA to induce CIH pretreated with or without TET. Liver injury was assessed biochemically and histologically. Levels of plasma cytokines and the expressions of chemokine messenger RNA (mRNA) in the liver were determined. We found that pretreatment of mice with TET markedly reduced plasma transaminase release and the severity of liver damage. We further investigated the mechanisms of the protective effects of TET. When CIH-induced mice pretreated with TET, the increases of plasma concentrations of TNF-alpha, IFN-gamma, IL-12 and IL-4 were dramatically attenuated; at the same time, IFN-inducible protein-10 and macrophage inflammatory protein-1alpha expressions in liver were decreased. Furthermore, TET inhibited NF-kappaB activity, the critical transcriptional factor of the above mentioned inflammatory cytokines, by preventing the activation of IkappaBalpha kinasealpha (IKKalpha) and then inhibiting phosphorylation of IkappaBalpha to stabilize IkappaBalpha in intrahepatic leukocytes. In conclusion, TET is able to prevent T-cell-mediated liver injury in vivo. The beneficial effect may depend on suppressing the production of various inflammatory mediators in the liver through inhibiting of NF-kappaB activation.
Feng
Dechun
D
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Mei
Yunhua
Y
Wang
Ying
Y
Zhang
Bianhong
B
Wang
Chen
C
Xu
Lingyun
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D044182:Benzylisoquinolines / Q000276:immunology / Q000627:therapeutic use*; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D003208:Concanavalin A / Q000009:adverse effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D004790:Enzyme Induction / Q000187:drug effects / Q000276:immunology; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008517:Phytotherapy; D015398:Signal Transduction / Q000187:drug effects; D031609:Stephania tetrandra / Q000276:immunology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology
D044182:Benzylisoquinolines; D054405:Chemokine CCL3; D054357:Chemokine CXCL10; D016207:Cytokines; D004365:Drugs, Chinese Herbal; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D003208:Concanavalin A; C009438:tetrandrine; D051550:I-kappa B Kinase