title: 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.
authors.affiliation: Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, University of Birmingham, UK.
authors.forename: Annika
authors.initials: A
authors.lastname: Wilhelm
authors.affiliation: Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, University of Birmingham, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Shepherd
authors.affiliation: Department of Immunology, Biogen, Cambridge, MA, USA.
authors.forename: Aldo
authors.initials: A
authors.lastname: Amatucci
authors.affiliation: Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, University of Birmingham, UK.
authors.forename: Mamoona
authors.initials: M
authors.lastname: Munir
authors.affiliation: Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, University of Birmingham, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Reynolds
authors.affiliation: Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, University of Birmingham, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Humphreys
authors.affiliation: Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, University of Birmingham, UK.|Medizinische Klinik 5/Department of Internal Medicine 5, Universitätsklinikum Erlangen/University Medical Centre Erlangen, Germany.
authors.forename: Yazid
authors.initials: Y
authors.lastname: Resheq
authors.affiliation: Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, University of Birmingham, UK.
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.affiliation: Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, University of Birmingham, UK.|Department of Cellular Pathology, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hübscher
authors.affiliation: Department of Immunology, Biogen, Cambridge, MA, USA.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.affiliation: Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, University of Birmingham, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Weston
authors.affiliation: Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, University of Birmingham, UK.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Afford
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury; D056487:Chemical and Drug Induced Liver Injury, Chronic; D000074049:Cytokine TWEAK; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000473:pathology*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology* / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000378:metabolism; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000172:deficiency* / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D000074049:Cytokine TWEAK; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D002251:Carbon Tetrachloride
keywords: TNF family; liver fibrosis; myofibroblast