concanavalin-a and tetrandrine

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.

Topics: Animals; Apoptosis; Benzylisoquinolines; Cells, Cultured; Chemokine CCL3; Chemokine CXCL10; Concanavalin A; Cytokines; Drugs, Chinese Herbal; Enzyme Induction; Hepatitis, Animal; Hepatocytes; I-kappa B Kinase; Immunosuppressive Agents; Mice; Mice, Inbred C57BL; NF-kappa B; Phytotherapy; Signal Transduction; Stephania tetrandra; Transcriptional Activation

We compared the effects of two bisbenzylisoquinoline compounds on leukotriene and prostaglandin generation by human monocytes and neutrophils. The results show that tetrandrine had a much greater effect than berbamine on leukotriene generation. However, both compounds were equally potent in suppression of prostaglandin generation. This inhibitory effect on prostaglandin generation can be overcome by exogenous arachidonic acid (AA), suggesting that the site of inhibition is not on the cyclooxygenase enzyme complex, but more proximally on the phospholipase-mediated release of AA from the cell membrane, similar to the action of corticosteroids. These results, together with previous findings of inhibitory effects on other inflammatory mediators such as histamine, platelet-activating-factor (PAF) and interleukin 1 (IL-1) indicate that these plant alkaloids may be useful lead compounds for the development of a new class of anti-inflammatory drugs.

Topics: Alkaloids; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arachidonic Acids; Benzylisoquinolines; Concanavalin A; Dinoprostone; Humans; Leukotrienes; Monocytes; Neutrophils; Prostaglandins