Tetrandrine regulates hepatic stellate cell activation via TAK1 and NF-κB signaling

• Published in: International immunopharmacology Vol. 36; pp. 263 - 270
• Main Authors: Li, Xia, Jin, Quan, Wu, Yan-Ling, Sun, Peng, Jiang, Shuang, Zhang, Yu, Zhang, De-Quan, Zhang, Yu-Jing, Lian, Li-Hua, Nan, Ji-Xing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2016
• Subjects: Actins - metabolism; Animals; Apoptosis - drug effects; Benzylisoquinolines - pharmacology; Caspase 3 - metabolism; Cell Line, Transformed; Drugs, Chinese Herbal - pharmacology; Fibrosis; Hepatic stellate cell; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - pathology; Hepatocytes - drug effects; Hepatocytes - physiology; JNK; MAP Kinase Kinase 4 - metabolism; MAP Kinase Kinase Kinases - metabolism; NF-kappa B - metabolism; NF-κB; Rats; Signal Transduction - drug effects; Stephania tetrandra - immunology; TAK1; Tetrandrine; Tumor Necrosis Factor-alpha - immunology; Tetrandrine; JNK; TRADD; MAPK; ECM; α-SMA; NF-κB; TNF-α; TAK1; HSC; FADD; Hepatic stellate cell; ERK
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2016.04.039

We investigated the anti-fibrotic mechanism of tetrandrine, a bisbenzylisoquinoline alkaloid from the Chinese herb, Stephania tetrandra, on the immortalized HSC-T6 rat hepatic stellate cell line. Tetrandrine (0.39–50μM) dose- and time-dependently inhibited HSC-T6 cell viability within 24h and exhibited almost no cytotoxicity at concentrations lower than 6.25μM in the presence of tumor necrosis factor-α (TNF-α). At a much high concentration (50μM), tetrandrine caused fatal cytotoxity in both HSCs and hepatocytes. TNF-α time-dependently increased α-smooth muscle actin (α-SMA) expression, while a lower concentration of tetrandrine (6.25μM) prior to TNF-α treatment reduced the expression of α-SMA and TNFR-1-associated death domain (TRADD). TNF-α treatment induced TGF-β-activated kinase-1 (TAK1) and c-Jun N-terminal kinase (JNK) phosphorylation, which were attenuated by tetrandrine. Furthermore, TNF-α treatment activated nuclear factor-κB (NF-κB) nuclear translocation and IκB-α degradation. Tetrandrine treatment prior to TNF-α reduced nuclear phosphorylated and total NF-κB p65, while the cytosolic IκB-α and NF-κB p65 levels significantly increased. In addition, treatment with only tetrandrine induced the cleavage of caspase-3 and PARP within a range of higher concentrations. Tetrandrine-induced apoptosis was confirmed by the TUNEL assay and flow-cytometric analysis. Treatment with only tetrandrine markedly reduced α-SMA expression, except for at lower concentrations of tetrandrine. A higher concentration of tetrandrine (25μM) induced a significant increase in JNK and extracellular signal-regulated kinase (ERK) phosphorylation, NF-κB nuclear translocation and IκB-α degradation. In conclusion, the anti-fibrogenic effects of tetrandrine on HSCs involved a dosage-dependent signaling pathway, based on the tetrandrine concentration, by regulating TAK1, JNK and NF-κB. The present data provides strong evidence for the anti-fibrotic dosage-dependent signaling pathway of tetrandrine. •Low concentrations of tetrandrine inhibited TNF-α-stimulated TAK1 and NF-κB activation in hepatic stellate cells (HSC).•At higher concentrations, tetrandrine triggered HSC apoptosis via TAK1 and NF-κB activation.•At even higher concentrations, tetrandrine was cytotoxic to HSCs and hepatocytes.•Anti-fibrogenic effects of tetrandrine were concentration dependent.