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

Abstract

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 (HSCs) were investigated by qPCR, western blotting and immunohistochemistry. In addition, the levels of Fn14 in HSCs following pro‐fibrogenic and pro‐inflammatory stimuli were assessed and the effects of exogenous TWEAK on HSCs 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 co‐localized with markers of activated HSCs. Fn14 levels were low in quiescent HSCs but were significantly induced in activated HSCs, which could be further enhanced with the profibrogenic cytokine TGFβ in vitro. Stimulation with recombinant TWEAK induced proliferation but not further HSCs activation. Fn14 gene expression was also significantly up‐regulated 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 HSCs proliferation, making it a potential therapeutic target for liver fibrosis. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Infliximab and Dexamethasone Attenuate the Ductular Reaction in Mice

“…S9). Of note, recent in vitro experiments with HSCs showed that Tweak could affect proliferation and not activation of HSCs36 while in our experiments HSC is not affected even though DEX decreased Tweak mRNA levels. Moreover, the DEX mediated inhibition of these signaling pathways apparently outperforms the potential downstream negative effects of an increased hepatocytic injury (higher ALT values) in the co-treated DEX/DDC animals (Figs 4 and 5).…”

“…Neither IFX, nor DEX, affected the proliferation of F4/80 + cells suggesting that the difference in the F4/80 + cells is mainly due to a difference in recruitment of macrophages. A possible mediator in the effect of DEX on these injury models is Tweak, a known mitogen for HSPCs that acts through the FN14 receptor35 and is necessary for liver fibrosis following chronic CCl 4 injury36. Tweak mRNA levels are decreased by DEX in both injury models, which could explain the lesser DR and fibrogenesis when DEX is used (Fig.…”

Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats

“…Decorin was another protein whose cardiac expression was modulated similarly in both ZO-C and ZL-C. Rapamycin increased this cardioprotective protein in both groups (Figure 6). Expression of profibrotic receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK-R/Fn4) [46] was increased by over 2.4-fold by Rapamycin in the ZL-C heart. The T cell Ig and mucin domain-1 (Tim-1) protein is implicated in allograft rejection [47] and its expression also was increased by 2-fold by Rapamycin treatment.…”

Hepatic stellate cells as key target in liver fibrosis

“…TWEAK also leads to liver fibrosis progression by directly promoting HSC proliferation. TWEAK, and by enhancing SIRT1 expression and decreasing p53 acetylation, which assumedly inhibits HSC senescence [199, 200]. …”