title: Induction of interferon-λ contributes to Toll-like receptor-3-activated hepatic stellate cell-mediated hepatitis C virus inhibition in hepatocytes.
abstract: There is limited information about the role of hepatic stellate cells (HSC) in liver innate immunity against hepatitis C virus (HCV). We thus examined whether HSC can produce antiviral factors that inhibit HCV replication in human hepatocytes. HSC expressed functional Toll-like receptor 3 (TLR-3), which could be activated by its ligand, polyinosine-polycytidylic acid (poly I:C), leading to the induction of interferon-λ (IFN-λ) at both mRNA and protein levels. TLR-3 signalling of HSC also induced the expression of IFN regulatory factor 7 (IRF-7), a key regulator of IFN signalling pathway. When HCV JFH-1-infected Huh7 cells were co-cultured with HSC activated with poly I:C or incubated in media conditioned with supernatant (SN) from poly I:C-activated HSC, HCV replication was significantly suppressed. This HSC SN action on HCV inhibition was mediated through IFN-λ, which was evidenced by the observation that antibody to IFN-λ receptors could neutralize the HSC-mediated anti-HCV effect. The role of IFN-λ in HSC-mediated anti-HCV activity is further supported by the observation that HSC SN treatment induced the expression of IRF-7 and IFN-stimulated genes (ISGs), OAS-1 and MxA in HCV-infected Huh7 cells. These observations indicate that HSC may be a key regulatory bystander, participating in liver innate immunity against HCV infection using an IFN-λ-dependent mechanism.
authors: The Center for Animal Experiment and ABSL-3 Laboratory, Wuhan University, Hubei, China.
authors: Y
authors: Y
authors: Wang
authors: J
authors: J
authors: Li
authors: X
authors: X
authors: Wang
authors: L
authors: L
authors: Ye
authors: Y
authors: Y
authors: Zhou
authors: W
authors: W
authors: Ho
mesh_terms: D045744:Cell Line, Tumor; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D016174:Hepacivirus / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000276:immunology* / Q000821:virology; D022781:Hepatocytes / Q000276:immunology / Q000821:virology*; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000821:virology; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000276:immunology*; D014779:Virus Replication
chemical_list: D017077:Culture Media, Conditioned; D050839:Interferon Regulatory Factor-7; C494235:Irf7 protein, mouse; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D007371:Interferon-gamma; D011070:Poly I-C
references: Immunity. 2007 Jan;26(1):117-29
references: 17239632
references: J Biol Chem. 2008 Oct 31;283(44):30079-89
references: 18757365
references: J Neurosci Res. 2012 Feb;90(2):399-406
references: 22057682
references: J Virol. 2009 Apr;83(8):3834-42
references: 19193806
references: Hepatology. 2005 Oct;42(4):819-27
references: 16175599
references: Immunology. 2010 Sep;131(1):40-9
references: 20636339
references: Semin Liver Dis. 2001 Aug;21(3):311-35
references: 11586463
references: Biol Reprod. 2008 Oct;79(4):766-75
references: 18596219
references: J Hepatol. 2002 Sep;37(3):322-30
references: 12175627
references: Gut. 2002 Apr;50(4):571-81
references: 11889082
references: Gut. 2005 Jan;54(1):142-51
references: 15591520
references: Am J Physiol Gastrointest Liver Physiol. 2007 Oct;293(4):G809-16
references: 17673545
references: J Virol Methods. 2002 Apr;102(1-2):119-28
references: 11879700
references: Gastroenterology. 2008 May;134(6):1655-69
references: 18471545
references: Hepatology. 2007 Nov;46(5):1509-18
references: 17705260
references: Hepatology. 2011 Dec;54(6):1913-23
references: 21800339
references: Hepatology. 2009 Mar;49(3):753-62
references: 19085952
references: J Hepatol. 2011 Aug;55(2):289-98
references: 21147189
references: J Immunol. 2011 May 15;186(10):5549-55
references: 21460203
references: Virol J. 2005 Sep 07;2:80
references: 16146571
references: Nat Genet. 2009 Oct;41(10):1100-4
references: 19749758
references: J Virol. 2005 Mar;79(6):3851-4
references: 15731279
references: J Virol. 2008 Jun;82(11):5440-9
references: 18367536
references: Ann N Y Acad Sci. 2009 Dec;1182:80-7
references: 20074277
references: Nature. 2009 Sep 17;461(7262):399-401
references: 19684573
references: Nat Rev Immunol. 2002 Sep;2(9):675-87
references: 12209136
references: Immunology. 2006 Jan;117(1):11-21
references: 16423036
references: J Hepatol. 2009 Dec;51(6):1037-45
references: 19716616
references: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2992-7
references: 15710891
references: Gastroenterology. 2006 Dec;131(6):1887-98
references: 17087946
references: Annu Rev Immunol. 2002;20:197-216
references: 11861602
references: J Immunol. 2008 Feb 15;180(4):2474-85
references: 18250457
references: Nature. 2001 Oct 18;413(6857):732-8
references: 11607032
references: Med Electron Microsc. 2004 Mar;37(1):3-15
references: 15057600
references: Neuroscience. 2009 Mar 17;159(2):629-37
references: 19166911
references: J Immunol. 2005 May 15;174(10):6322-31
references: 15879132
references: Hepatology. 2010 Sep;52(3):822-32
references: 20564352
references: Gastroenterology. 2004 Feb;126(2):529-40
references: 14762790
references: J Neurosci Res. 2009 Oct;87(13):2916-25
references: 19437550
references: Nat Med. 2007 Nov;13(11):1324-32
references: 17952090
references: Nature. 2009 Oct 8;461(7265):798-801
references: 19759533
references: J Virol. 2009 Oct;83(19):9824-34
references: 19625408
references: J Virol. 2006 May;80(9):4501-9
references: 16611910
references: Nat Med. 2007 May;13(5):552-9
references: 17479101
references: Nature. 2006 May 4;441(7089):101-5
references: 16625202
references: Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9294-9
references: 15939869
references: Nat Immunol. 2003 Jan;4(1):69-77
references: 12483210
references: Nat Genet. 2009 Oct;41(10):1105-9
references: 19749757
references: Nat Immunol. 2006 Feb;7(2):131-7
references: 16424890
references: Hepatology. 2006 Oct;44(4):896-906
references: 17006906