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The Notch pathway mediated by recombination signal binding protein J\u03ba (RBP\u2010J), 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\u2010specific disruption of RBP\u2010J resulted in attenuated fibrosis. The activation of hepatic stellate cells and production of profibrotic factors including platelet\u2010derived growth factor (PDGF)\u2010B and transforming growth factor beta1 (TGF\u2010\u03b21) reduced significantly in myeloid\u2010specific RBP\u2010J deficient mice. The infiltration of inflammatory cells and production of proinflammatory factors were reduced in liver of myeloid\u2010specific RBP\u2010J\u2010deficient mice during fibrosis. In RBP\u2010J\u2010deficient macrophages, the nuclear factor kappa B (NF\u2010\u03baB) activation was remarkably attenuated as compared with the control. This could be attributed to the up\u2010regulation of cylindromatosis (CYLD), a negative regulator of NF\u2010\u03baB, in Notch signal\u2010compromised macrophages, because the knockdown of CYLD in RBP\u2010J\u2010deficient macrophages or overexpression of p65 in RBP\u2010J knockdown cells both restored NF\u2010\u03baB 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. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: RBP\u2010J\u2010mediated Notch signaling is required for macrophages to promote hepatic fibrosis by up\u2010regulation of NF\u2010\u03baB activation through CYLD. (H<jats:sc>epatology<\/jats:sc> 2015;61:303\u2013314)<\/jats:p>","DOI":"10.1002\/hep.27394","type":"journal-article","created":{"date-parts":[[2014,8,22]],"date-time":"2014-08-22T09:27:10Z","timestamp":1408699630000},"page":"303-314","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":49,"title":["Myeloid\u2010specific disruption of recombination signal binding protein J\u03ba ameliorates hepatic fibrosis by attenuating inflammation through cylindromatosis in mice"],"prefix":"10.1097","volume":"61","author":[{"given":"Fei","family":"He","sequence":"first","affiliation":[{"name":"Department of Hepatic Surgery,Xijing Hospital, Fourth Military Medical University,Xi'an,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng\u2010Cheng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Hepatic Surgery,Xijing Hospital, Fourth Military Medical 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Developmental Biology,Fourth Military Medical University,Xi'an,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Feng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology,Department of Medical Genetics and Developmental Biology,Fourth Military Medical University,Xi'an,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Na","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology,Department of Medical Genetics and Developmental Biology,Fourth Military Medical University,Xi'an,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology,Department of Medical Genetics and Developmental Biology,Fourth Military Medical 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