title: Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice.
abstract: Activation of innate immunity (natural killer [NK] cell/interferon-γ [IFN-γ]) has been shown to play an important role in antiviral and antitumor defenses as well as antifibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2-week or a 10-week carbon tetrachloride (CCl(4) ) challenge, respectively. Injection of polyinosinic-polycytidylic acid (poly I:C) or IFN-γ induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2-week CCl(4) model. Such activation was diminished in the 10-week CCl(4) model. Consistent with these findings, the inhibitory effect of poly I:C and IFN-γ on liver fibrosis was markedly reduced in the 10-week versus the 2-week CCl(4) model. In vitro coculture experiments demonstrated that 4-day cultured (early activated) HSCs induce NK cell activation via an NK group 2 member D/retinoic acid-induced early gene 1-dependent mechanism. Such activation was reduced when cocultured with 8-day cultured (intermediately activated) HSCs due to the production of transforming growth factor-β (TGF-β) by HSCs. Moreover, early activated HSCs were sensitive, whereas intermediately activated HSCs were resistant to IFN-γ-mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN-γ inhibition of cell proliferation in intermediately activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN-γ signaling and functioning, whereas production of TGF-β by HSCs inhibited NK cell function and cytotoxicity against HSCs.
  
  
  CONCLUSIONS
  The antifibrogenic effects of NK cell/IFN-γ are suppressed during advanced liver injury, which is likely due to increased production of TGF-β and expression of SOCS1 in intermediately activated HSCs.
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea; Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD. wijeong@kaist.ac.kr
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.forename: Yang-Gun
authors.initials: YG
authors.lastname: Suh
authors.forename: Jin-Seok
authors.initials: JS
authors.lastname: Byun
authors.forename: So-Young
authors.initials: SY
authors.lastname: Park
authors.forename: Earl
authors.initials: E
authors.lastname: Choi
authors.forename: Ja-Kyung
authors.initials: JK
authors.lastname: Kim
authors.forename: Hyojin
authors.initials: H
authors.lastname: Ko
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Miller
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
mesh_terms: D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000276:immunology; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D008103:Liver Cirrhosis / Q000276:immunology*; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism
chemical_list: C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016212:Transforming Growth Factor beta; D014801:Vitamin A; D007371:Interferon-gamma; D011070:Poly I-C