title: Critical role of tumor necrosis factor receptor 1, but not 2, in hepatic stellate cell proliferation, extracellular matrix remodeling, and liver fibrogenesis.
abstract: Tumor necrosis factor (TNF) has been implicated in the progression of many chronic liver diseases leading to fibrosis; however, the role of TNF in fibrogenesis is controversial and the specific contribution of TNF receptors to hepatic stellate cell (HSC) activation remains to be established. Using HSCs from wild-type, TNF-receptor-1 (TNFR1) knockout, TNF-receptor-2 (TNFR2) knockout, or TNFR1/R2 double-knockout (TNFR-DKO) mice, we show that loss of both TNF receptors reduced procollagen-α1(I) expression, slowed down HSC proliferation, and impaired platelet-derived growth factor (PDGF)-induced promitogenic signaling in HSCs. TNFR-DKO HSCs exhibited decreased AKT phosphorylation and in vitro proliferation in response to PDGF. These effects were reproduced in TNFR1 knockout, but not TNFR2 knockout, HSCs. In addition, matrix metalloproteinase 9 (MMP-9) expression was dependent on TNF binding to TNFR1 in primary mouse HSCs. These results were validated in the human HSC cell line, LX2, using neutralizing antibodies against TNFR1 and TNFR2. Moreover, in vivo liver damage and fibrogenesis after bile-duct ligation were reduced in TNFR-DKO and TNFR1 knockout mice, compared to wild-type or TNFR2 knockout mice.
  
  
  CONCLUSIONS
  TNF regulates HSC biology through its binding to TNFR1, which is required for HSC proliferation and MMP-9 expression. These data indicate a regulatory role for TNF in extracellular matrix remodeling and liver fibrosis, suggesting that targeting TNFR1 may be of benefit to attenuate liver fibrogenesis.
authors.affiliation: IDIBAPS, Liver Unit-Hospital Clínic, CIBEREHD, Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Tarrats
authors.forename: Anna
authors.initials: A
authors.lastname: Moles
authors.forename: Albert
authors.initials: A
authors.lastname: Morales
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Ruiz
authors.forename: José C
authors.initials: JC
authors.lastname: Fernández-Checa
authors.forename: Montserrat
authors.initials: M
authors.lastname: Marí
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001652:Bile Ducts / Q000503:physiopathology; D002460:Cell Line; D049109:Cell Proliferation; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000502:physiology*; D055166:Hepatic Stellate Cells / Q000473:pathology* / Q000502:physiology; D006801:Humans; D008026:Ligation; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000276:immunology / Q000502:physiology*
chemical_list: D000906:Antibodies; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9