Impairment of the retinoic acid-inducible gene-I-IFN-β signaling pathway in chronic hepatitis B virus infection

Zhao,Gangde; An,Baoyan; Zhou,Huijuan; Wang,Hui; Xu,Yumin; Xiang,Xiaogang; Dong,Zhixia; An,Fangmei; Yu,Dongshan; Wang,Weijing; Bao,Shisan; Xie,Qing

doi:10.3892/ijmm.2012.1131

Impairment of the retinoic acid-inducible gene-I-IFN-β signaling pathway in chronic hepatitis B virus infection

Authors:
- Gangde Zhao
- Baoyan An
- Huijuan Zhou
- Hui Wang
- Yumin Xu
- Xiaogang Xiang
- Zhixia Dong
- Fangmei An
- Dongshan Yu
- Weijing Wang
- Shisan Bao
- Qing Xie
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Affiliations: Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China, Discipline of Pathology, School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia
Published online on: September 19, 2012 https://doi.org/10.3892/ijmm.2012.1131
Pages: 1498-1504

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Abstract

Chronic hepatitis B (CHB) virus infection is caused by compromised host immunity, but the precise underlying mechanism remains unclear. Retinoic acid-inducible gene I (RIG-I) triggers antiviral immunity by inducing interferon-β (IFN-β) production following viral infection. To investigate the role of the RIG-I-IFN-β signaling pathway in monocyte-derived dendritic cells (moDCs) during CHB infection, moDCs were generated by stimulating CD14+ monocytes in vitro. MoDCs from patients with CHB, acute hepatitis B (AHB) and healthy controls (HCs) were challenged with vesicular stomatitis virus (VSV) and the levels of RIG-I, IFN-β promoter stimulator 1 (IPS-1) and IFN-β in the stimulated moDCs were determined. Following 16 h of VSV stimulation, RIG-I expression was reduced by 50% in moDCs from CHB patients and by 70% in moDCs from AHB patients relative to HC moDCs, concomitant with a 20% decrease in IFN-β expression in CHB patients relative to AHB patients and HCs. Additionally, a significant correlation between the RIG-I/IPS-1 ratio and alanine aminotransferase (ALT) level was observed. To further investigate the function of RIG-I in chronic hepatitis B virus (HBV) infection, HepG2 or HepG2.2.15 (HBV-transformed) cell lines were challenged with VSV following RIG-1 transfection. IFN-β induction was suppressed in HepG2.2.15 cells, but was restored following RIG-I transfection. Taken together, these data indicate that compromised moDC function in CHB patients is attributable to an impaired RIG-I-IFN-β signaling pathway, which results in compromised host viral clearance and HBV persistence in a susceptible population.

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1.	AS LokBJ McMahonChronic hepatitis B: update 2009Hepatology50661662200910.1002/hep.2319019714720
2.	G MarinosF TorreS ChokshiInduction of T-helper cell response to hepatitis B core antigen in chronic hepatitis B: a major factor in activation of the host immune response to the hepatitis B virusHepatology2210401049199510.1002/hep.18402204057557849
3.	T HatakeyamaC NoguchiN HiragaSerum HBV RNA is a predictor of early emergence of the YMDD mutant in patients treated with lamivudineHepatology4511791186200710.1002/hep.2158117465002
4.	G ChengJ ZhongJ ChungFV ChisariDouble-stranded DNA and double-stranded RNA induce a common antiviral signaling pathway in human cellsProc Natl Acad Sci USA10490359040200710.1073/pnas.070328510417517627
5.	MS LeeYJ KimSignaling pathways downstream of pattern-recognition receptors and their cross talkAnnu Rev Biochem76447480200710.1146/annurev.biochem.76.060605.12284717328678
6.	V HornungJ EllegastS Kim5′-Triphosphate RNA is the ligand for RIG-IScience3149949972006
7.	M YoneyamaM KikuchiT NatsukawaThe RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responsesNat Immunol5730737200410.1038/ni108715208624
8.	H KatoS SatoM YoneyamaCell type-specific involvement of RIG-I in antiviral responseImmunity231928200510.1016/j.immuni.2005.04.01016039576
9.	T FujitaK OnoguchiK OnomotoR HiraiM YoneyamaTriggering antiviral response by RIG-I-related RNA helicasesBiochimie89754760200710.1016/j.biochi.2007.01.01317379377
10.	M BinderG KochsR BartenschlagerV LohmannHepatitis C virus escape from the interferon regulatory factor 3 pathway by a passive and active evasion strategyHepatology4613651374200710.1002/hep.2182917668876
11.	A KomuroD BammingCM HorvathNegative regulation of cytoplasmic RNA-mediated antiviral signalingCytokine43350358200810.1016/j.cyto.2008.07.01118703349
12.	W CaiQ XieB AnOn-treatment serum HBsAg level is predictive of sustained off-treatment virologic response to telbivudine in HBeAg-positive chronic hepatitis B patientsJ Clin Virol482226201010.1016/j.jcv.2010.02.01420233672
13.	LY LinVW WongHJ ZhouRelationship between serum hepatitis B virus DNA and surface antigen with covalently closed circular DNA in HBeAg-negative patientsJ Med Virol8214941500201010.1002/jmv.2186320648602
14.	M DauerB ObermaierJ HertenMature dendritic cells derived from human monocytes within 48 hours: a novel strategy for dendritic cell differentiation from blood precursorsJ Immunol17040694076200310.4049/jimmunol.170.8.406912682236
15.	P NakhaeiT MespledeM SolisThe E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradationPLoS Pathog5e1000650200910.1371/journal.ppat.100065019893624
16.	D SunM NassalStable HepG2- and Huh7-based human hepatoma cell lines for efficient regulated expression of infectious hepatitis B virusJ Hepatol45636645200610.1016/j.jhep.2006.05.01916935386
17.	BR tenOeverS SharmaW ZouActivation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunityJ Virol781063610649200410.1128/JVI.78.19.10636-10649.2004
18.	Q HuangQ XieCC ShiExpression of angiotensin-converting enzyme 2 in CCL4-induced rat liver fibrosisInt J Mol Med23717723200919424597
19.	MC JungGR PapeImmunology of hepatitis B infectionLancet Infect Dis24350200210.1016/S1473-3099(01)00172-4
20.	D TerhorstBN KalaliS WeidingerMonocyte-derived dendritic cells from highly atopic individuals are not impaired in their pro-inflammatory response to toll-like receptor ligandsClin Exp Allergy37381390200710.1111/j.1365-2222.2006.02639.x17359388
21.	S PattersonH DonaghyP AmjadiB GazzardF GotchP KelleherHuman BDCA-1-positive blood dendritic cells differentiate into phenotypically distinct immature and mature populations in the absence of exogenous maturational stimuli: differentiation failure in HIV infectionJ Immunol17482008209200510.4049/jimmunol.174.12.8200
22.	Y ShimizuLG GuidottiP FowlerFV ChisariDendritic cell immunization breaks cytotoxic T lymphocyte tolerance in hepatitis B virus transgenic miceJ Immunol1614520452919989794377
23.	RE RandallS GoodbournInterferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasuresJ Gen Virol89147200810.1099/vir.0.83391-018089727
24.	CK HuiGK LauImmune system and hepatitis B virus infectionJ Clin Virol34S44S48200510.1016/S1386-6532(05)80009-516461223
25.	R LinJ LacosteP NakhaeiDissociation of a MAVS/ IPS-1/VISA/Cardif-IKKepsilon molecular complex from the mitochondrial outer membrane by hepatitis C virus NS3-4A proteolytic cleavageJ Virol8060726083200610.1128/JVI.02495-0516731946
26.	Y AsahinaN IzumiI HirayamaPotential relevance of cytoplasmic viral sensors and related regulators involving innate immunity in antiviral responseGastroenterology13413961405200810.1053/j.gastro.2008.02.01918471516
27.	JN StoopRG van der MolenCC BaanRegulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infectionHepatology41771778200510.1002/hep.2064915791617
28.	A ZerbiniM PilliC BoniThe characteristics of the cell-mediated immune response identify different profiles of occult hepatitis B virus infectionGastroenterology13414701481200810.1053/j.gastro.2008.02.01718355815
29.	JJ ChangSR LewinImmunopathogenesis of hepatitis B virus infectionImmunol Cell Biol851623200710.1038/sj.icb.710000917130898