Zhankuic acid A as a novel JAK2 inhibitor for the treatment of concanavalin A-induced hepatitis

• Published in: Biochemical pharmacology 2014-09, Vol.91 (2), p.217-230
• Main Authors: Chen, Yu-Fon, Wang, Sheng-Hung, Chang, Sue-Joan, Shiau, Ai-Li, Her, Lu-Shiun, Shieh, Gia-Shing, Chen, Chin-Fu, Chang, Chao-Ching, Su, Yu-Chu, Wu, Chao-Liang, Wu, Tian-Shung
• Format: Article
• Language: English
• Subjects: Animals; Anti-inflammation; Apoptosis - drug effects; Cell Line; Cell Proliferation; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - pathology; Concanavalin A - toxicity; Ergosterol - analogs & derivatives; Ergosterol - chemistry; Ergosterol - pharmacology; Ergosterol - therapeutic use; Gene Expression; Humans; Interferon regulatory factor-1; Interferon-γ; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - chemistry; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mitogens - toxicity; Molecular Structure; Signal transducer and activator of transcription 1; Spleen - cytology; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - physiology; Taiwanofungus camphoratus
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2014.06.026

Fruiting bodies of Taiwanofungus camphoratus have been widely used as an antidote for food poisoning and considered to be a precious folk medicine for anti-inflammation and hepatoprotection. Zhankuic acid A (ZAA) is its major pharmacologically active compound. Janus kinase 2 (JAK2), whose activation is involved in cytokine signaling, plays critical roles in the development and biology of the hematopoietic system. JAK2 has been implicated as a therapeutic target in inflammatory diseases. The HotLig modeling approach was used to generate the binding model for ZAA with JAK2, showing that ZAA could bind to the ATP-binding pocket of JAK2 exclusively via the H-bond. The interaction between ZAA and JAK2 was verified by antibody competition assay. Binding of ZAA to JAK2 reduced antibody recognition of native JAK2. The expressions of phosphorylated JAK2 and STATs were analyzed by immuno-blotting. ZAA reduced the phosphorylation and downstream signaling of JAK2, and inhibited the interferon (IFN)-γ/signal transducer and activator of transcription (STAT) 1/interferon regulatory factor (IRF)-1 pathway. The protective effect of ZAA on liver injury was evaluated in mice by Con-A-induced acute hepatitis. Pre-treatment with ZAA also significantly ameliorated acute liver injury in mice. Therefore, ZAA can inhibit JAK2 phosphorylation and protect against liver injury during acute hepatitis in mice. In this study, we present data that ZAA exerts anti-inflammatory effects through the JAK2 signaling pathway. As such, ZAA may be a potential therapeutic agent for the treatment of inflammatory diseases.