LAUSR

HighlightsTWEAK induced the pro‐inflammatory cytokine secretion in HSCs.TWEAK activated NF‐&kgr;B and STAT3 signalling pathways in HSCs.The activation of STAT3 and NF‐&kgr;B interacted in HSCs.The pro‐inflammatory cytokine expression was p65‐ and STAT3‐dependent. Abstract Tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor‐inducible 14 (Fn14) have been associated with liver disease. Hepatic stellate cells (HSCs) play a critical role in the hepatic wound‐healing response after liver injury, but there is little information available on the role of the TWEAK/Fn14 pathway in human HSCs. In this study, we explored the role of TWEAK/Fn14 in activated human HSCs. The LX‐2 cells were treated with TWEAK, and the expression of pro‐inflammatory cytokines was assayed by enzyme‐linked immunosorbent assay (ELISA) and real‐time PCR (RT‐PCR). Western blotting and RT‐PCR were performed to evaluate the expression of Fn14 after TWEAK stimulation. Total and phosphorylated of inhibitor‐&kgr;B (I‐&kgr;B), nuclear factor kappa B (NF‐&kgr;B), Janus kinase 2 (JAK2), and signal transducers and activators of transcription 3 (STAT3) were examined by western blotting after TWEAK stimulation and small interfering RNA (siRNA) transfection. The result showed that TWEAK upregulated the expression of Fn14 and pro‐inflammatory factors interleukin‐8 (IL‐8), interleukin‐6 (IL‐6), regulated upon activation normal T cell expressed and secreted (RANTES), and monocyte chemotactic protein‐1 (MCP‐1). In LX‐2 cells, the pro‐inflammatory cytokine secretion was closely related to the activation of the NF‐&kgr;B and STAT3 pathways. Furthermore, our research showed that STAT3 and NF‐&kgr;B could interact with each other, which resulted in a significant increase of pro‐inflammatory cytokine secretion. The activation of NF‐&kgr;B and STAT3 signalling‐dependent pro‐inflammatory cytokine expression may be responsible for such a novel principle and new therapeutic targets in chronic liver disease.