Introduction The mortality from chronic liver disease in the UK has increased by 50%.1 The prevalence of cholangiopathies, diseases of the bile ducts, has increased fourfold.2 These include primary biliary cirrhosis, primary sclerosing cholangitis and allograft rejection after transplantation.3 4 It is increasingly observed in livers donated for transplantation after cardiac death, a source of organs on which the NHS is becoming more reliant.5 6 It is characterised by inflammation and destruction of intrahepatic bile ducts.7 When sustained it may drive portal fibrosis to end-stage liver disease when the only therapeutic option for patients is liver transplantation.8 The novel TNF superfamily member TNF-like weak inducer of apoptosis (TWEAK) and its cognate receptor FGF-inducible protein 14 (Fn14) are implicated in hepatic inflammation and remodelling.9 10 TWEAK is mainly secreted as a soluble cytokine by myelomonocytic cells.11 Fn14-TWEAK interaction in other systems promotes cell growth, apoptosis, autophagy and transdifferentiation via activation of TRAF and NF-kB pathways.12
Aim To demonstrate the expression of Fn14 and TWEAK on cholangiocytes and the functional significance of Fn14/TWEAK interaction on biliary ductular remodelling.
Methods Human liver samples were obtained with consent from the Queen Elizabeth Hospital liver transplant programme. Sections were stained for Fn14 and TWEAK using immunohistochemical techniques. Expression of Fn14 and TWEAK on cholangiocytes stimulated with TNF-α, IFN-γ and FGF was established quantitatively using flow cytometry. Cholangiocytes stimulated with FGF were exposed to TWEAK for 48 h. Apoptosis and reactive oxygen species production at this time point were determined by flow cytometry using annexin and dichlorofluorescein assays respectively.
Results Immunohistochemistry reveals Fn14 on the intra-hepatic small bile ducts of inflamed livers, especially around the Canals of Hering. Fn14 expression is increased on cholangiocytes in vitro by 26% after stimulation with FGF. Exposure of cholangiocytes to TWEAK for 48 h induces apoptosis and upregulation of reactive oxygen species in FGF-activated cholangiocytes.
Conclusion Fn14 is expressed on cholangiocytes in inflamed human livers. Activation of the Fn14/TWEAK receptor-ligand system induces apoptosis using a novel mechanism partly dependent on the generation of reactive oxygen species.
Competing interests None declared.
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