title: Toll-like receptor 7-mediated type I interferon signaling prevents cholestasis- and hepatotoxin-induced liver fibrosis.
abstract: Toll-like receptor 7 (TLR7) signaling predominantly regulates production of type I interferons (IFNs), which has been suggested in clinical studies to be antifibrotic. However, the mechanistic role of the TLR7-type I IFN axis in liver fibrosis has not been elucidated. In the present study, liver fibrosis was induced in wild-type (WT), TLR7-deficient, and IFN-α/β receptor-1 (IFNAR1)-deficient mice and TLR7-mediated signaling was assessed in liver cells isolated from these mice. TLR7-deficient and IFNAR1-deficient mice were more susceptible to liver fibrosis than WT mice, indicating that TLR7-type I IFN signaling exerts a protective effect against liver fibrosis. Notably, the hepatic expression of interleukin-1 receptor antagonist (IL-1ra) was suppressed in TLR7- or IFNAR1-deficient mice compared with respective WT mice, and treatment with recombinant IL-1ra reduced liver fibrosis. In vivo activation of TLR7 significantly increased IFNa4 and IL-1ra expression in the liver. Interestingly, each cytokine had a different cellular source, showing that dendritic cells (DCs) are the responsible cell type for production of type I IFN, while Kupffer cells (KCs) mainly produce IL-1ra in response to type I IFN. Furthermore, TLR7 activation by R848 injection suppressed liver fibrosis and production of proinflammatory cytokines, and these effects were dependent on type I IFN signaling. Consistent with in vivo data, IFN-α significantly induced IL-1ra production in primary KCs.
  
  
  CONCLUSIONS
  TLR7 signaling activates DCs to produce type I IFN, which in turn induces antifibrogenic IL-1ra production in KCs. Thus, manipulation of the TLR7-type I IFN-IL-1ra axis may be a new therapeutic strategy for the treatment of liver fibrosis.
authors.affiliation: Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine (BK21 Plus Program), Chonbuk National University, Jeonju, South Korea; Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA, USA.
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Roh
authors.forename: Surim
authors.initials: S
authors.lastname: Park
authors.forename: Jong Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Chae Woong
authors.initials: CW
authors.lastname: Lim
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.forename: Bumseok
authors.initials: B
authors.lastname: Kim
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D002779:Cholestasis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D002908:Chronic Disease; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007370:Interferon Type I / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000276:immunology / Q000378:metabolism; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism; D008103:Liver Cirrhosis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C508032:Ifnar1 protein, mouse; C507764:Il1rn protein, mouse; D007370:Interferon Type I; D053590:Interleukin 1 Receptor Antagonist Protein; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D053633:Receptor, Interferon alpha-beta; D002251:Carbon Tetrachloride