The Role of TWEAK/Fn14 Signaling in Liver Regeneration after Mouse Partial Hepatectomy

Abstract

Introduction: Liver regeneration is important after liver resection and transplantation, though the mechanisms surrounding this process are complex and incompletely understood. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), acts via its specific receptor fibroblast growth factor-inducible 14 (Fn14), and Fn14 receptors have been shown to be highly expressed in chronically damaged livers, such as in hepatitis C, and in regenerating livers after partial hepatectomy (PH), suggesting a strong role for the TWEAK/Fn14 pathway in the proliferation of hepatic epithelial cells and/or their transformation. This is the first attempt to study the effect of stimulating the TWEAK/Fn14 pathway via administration of an agonistic anti-Fn14 monoclonal antibody (mAb), on liver regeneration after mouse PH. Methods: Mice were divided into 4 groups: sham (control), PH alone, PH + anti-Fn14 mAb, and sham + anti-Fn14 mAb, and sacrificed at 24, 48, 72 hrs (n=5 per group at each time point), or 7 days (n=2 per group). Anti-Fn14 mAb (ITEM-4: 200 μg/mouse) was administered at the time of initial surgery via intraperitoneal injection. Liver regeneration at point of sacrifice was estimated by remnant liver weight to body weight ratio (LBWr). Serum was taken for liver function assessment, and mice livers were resected for western blot assessment of the Fn14 receptor. Fn14 to actin ratios were calculated to standardize the results. Results: Resected LBWr, a marker for consistency of resection, was similar in both PH and PH + anti-Fn14 mAb groups (0.027 vs. 0.028, p=0.2). Remnant LBWr, a marker of regeneration, was significantly higher at 24 and 48 hrs after PH + anti-Fn14 mAb vs. PH alone, although it became similar at 72 hrs after PH. Western blot data indicates a trend toward higher expression of Fn14 at 24 hrs in the PH + anti-Fn14 mAb than in the sham group (Fn14:actin: 1.21 vs. 0.49, p=0.1) or PH alone group (Fn14:actin: 1.21 vs. 0.75, p=0.3). Values of LFTs (ALP, ALT, AST and total Bili) were similar between PH alone and PH + anti-Fn14 mAb groups at 24 and 48 hrs after PH, but all values were significantly higher in the PH + anti-Fn14 mAb group at 72 hrs compared with PH alone. At 7 days, all LFTs in both PH and PH + anti-Fn14 mAb groups returned to baseline. Conclusion: The TWEAK/Fn14 signaling pathway contributes to the early phase of liver regeneration by stimulating it after PH with upregulation of Fn14 in the liver. Agonistic anti-Fn14 mAb might be useful to stimulate liver regeneration after liver resection or liver transplantation with cautious monitoring of LFTs.