title: Myeloid-specific disruption of recombination signal binding protein Jκ ameliorates hepatic fibrosis by attenuating inflammation through cylindromatosis in mice.
abstract: Macrophages play multidimensional roles in hepatic fibrosis, but their control has not been fully understood. The Notch pathway mediated by recombination signal binding protein Jκ (RBP-J), the transcription factor transactivated by signals from four mammalian Notch receptors, is implicated in macrophage activation and plasticity. In this study, by using mouse hepatic fibrosis models, we show that myeloid-specific disruption of RBP-J resulted in attenuated fibrosis. The activation of hepatic stellate cells and production of profibrotic factors including platelet-derived growth factor (PDGF)-B and transforming growth factor beta1 (TGF-β1) reduced significantly in myeloid-specific RBP-J deficient mice. The infiltration of inflammatory cells and production of proinflammatory factors were reduced in liver of myeloid-specific RBP-J-deficient mice during fibrosis. In RBP-J-deficient macrophages, the nuclear factor kappa B (NF-κB) activation was remarkably attenuated as compared with the control. This could be attributed to the up-regulation of cylindromatosis (CYLD), a negative regulator of NF-κB, in Notch signal-compromised macrophages, because the knockdown of CYLD in RBP-J-deficient macrophages or overexpression of p65 in RBP-J knockdown cells both restored NF-κB activation and the production of proinflammatory and/or profibrotic factors by macrophages. In human hepatic fibrosis biopsies, stronger Notch activation is correlated with more severe fibrosis, which is accompanied by a lower level of CYLD but irrespective of etiological reasons.
  
  
  CONCLUSIONS
  RBP-J-mediated Notch signaling is required for macrophages to promote hepatic fibrosis by up-regulation of NF-κB activation through CYLD.
authors.affiliation: Department of Hepatic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Fei
authors.initials: F
authors.lastname: He
authors.forename: Feng-Cheng
authors.initials: FC
authors.lastname: Guo
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.forename: Heng-Chao
authors.initials: HC
authors.lastname: Yu
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Ma
authors.forename: Jun-Long
authors.initials: JL
authors.lastname: Zhao
authors.forename: Lei
authors.initials: L
authors.lastname: Feng
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Li
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Liu
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Qin
authors.forename: Ke-Feng
authors.initials: KF
authors.lastname: Dou
authors.forename: Hua
authors.initials: H
authors.lastname: Han
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D055166:Hepatic Stellate Cells / Q000502:physiology; D006505:Hepatitis / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D008103:Liver Cirrhosis / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C511601:CYLD protein, mouse; D003546:Cysteine Endopeptidases; D000074749:Deubiquitinating Enzyme CYLD; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D016328:NF-kappa B; C497571:Rbpj protein, mouse; D025521:Tumor Suppressor Proteins