Interaction of TWEAK with Fn14 leads to the progression of fibrotic liver disease by directly modulating hepatic stellate cell proliferation

Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) have been associated with liver regeneration in vivo. To further investigate the role of this pathway we examined their expression in human fibrotic liver disease and the effect of pathway deficiency in a murine model of liver fibrosis. The expression of Fn14 and TWEAK in normal and diseased human and mouse liver tissue and primary human hepatic stellate cells (HSC) were investigated by qPCR, western blotting and immunohistochemistry. In addition, the levels of Fn14 in HSC following pro-fibrogenic and pro-inflammatory stimuli were assessed and the effects of exogenous TWEAK on HSC proliferation and activation were studied in vitro. Carbon tetrachloride (CCl4) was used to induce acute and chronic liver injury in TWEAK KO mice. Elevated expression of both Fn14 and TWEAK were detected in acute and chronic human liver injury, and colocalised with markers of activated HSC. Fn14 levels were low in quiescent HSC but were significantly induced in activated HSC, which could be further enhanced with the profibrogenic cytokine TGF-β z. Stimulation with recombinant TWEAK induced proliferation but not further HSC activation. Fn14 gene expression was also significantly upregulated in CCl4 models of hepatic injury whereas TWEAK KO mice showed reduced levels of liver fibrosis following chronic CCl4 injury. In conclusion, TWEAK/Fn14 interaction leads to the progression of fibrotic liver disease via direct modulation of HSC proliferation, making it a potential therapeutic target for liver fibrosis.