HBV-Pol is crucial for HBV-mediated inhibition of inflammasome activation and IL-1β production.
Adult
Antiviral Agents
/ therapeutic use
Case-Control Studies
Female
Gene Products, pol
/ metabolism
Hep G2 Cells
Hepatitis B, Chronic
/ blood
Hepatitis C, Chronic
/ blood
Host-Pathogen Interactions
Humans
Inflammasomes
/ metabolism
Interferon-alpha
/ therapeutic use
Interleukin-18
/ blood
Interleukin-1beta
/ blood
Male
Middle Aged
Hepatitis B virus (HBV)
caspase-1
inflammasome
interleukin-1β (IL-1β)
polymerase
Journal
Liver international : official journal of the International Association for the Study of the Liver
ISSN: 1478-3231
Titre abrégé: Liver Int
Pays: United States
ID NLM: 101160857
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
09
01
2019
revised:
07
08
2019
accepted:
09
08
2019
pubmed:
17
8
2019
medline:
6
10
2020
entrez:
17
8
2019
Statut:
ppublish
Résumé
Hepatitis B virus (HBV) infection is the most critical factor underlying liver cirrhosis and hepatocellular carcinoma worldwide. IL-1β and IL-18, generated by activation of the inflammasome/caspase-1 signaling pathway, play important roles in the control and clearance of HBV. However, the specific relationship between the inflammasome response and IFN-α resistance or viral persistence is yet to be established. Blood samples of patients and supernatant fractions of HBV cell lines were collected for analysis and the effects on inflammasome activation and IL-1β production evaluated via enzyme-linked immunosorbent assay (ELISA), western blot, quantitative RT-PCR and immunofluorescence. IL-1β and IL-18 levels produced in sera of IFN-α non-responders were significantly lower than those of responders and normal donors. Additionally, expression of IL-1β and inflammasome components was decreased in peripheral blood mononuclear cells (PBMC) of non-responders, compared with those of responders. In vitro experiments on HepG2, HepG2.2.15 and HepAD38 cell lines showed that HBV induces a significant decrease in IL-1β production through inhibiting activation of the NF-κB signaling and inflammasome/caspase-1 pathways. And hepatitis B virus polymerase (HBV-Pol) appeared crucial for these inhibitory effects of HBV. IL-1β production is suppressed in HBV carriers and IFN-α non-responders. HBV induces a significant decrease in IL-1β production through inhibiting the NF-κB signaling and inflammasome pathways, for which HBV-Pol is a crucial requirement. Trial approval number: 20 173 402.
Sections du résumé
BACKGROUND & AIMS
Hepatitis B virus (HBV) infection is the most critical factor underlying liver cirrhosis and hepatocellular carcinoma worldwide. IL-1β and IL-18, generated by activation of the inflammasome/caspase-1 signaling pathway, play important roles in the control and clearance of HBV. However, the specific relationship between the inflammasome response and IFN-α resistance or viral persistence is yet to be established.
METHODS
Blood samples of patients and supernatant fractions of HBV cell lines were collected for analysis and the effects on inflammasome activation and IL-1β production evaluated via enzyme-linked immunosorbent assay (ELISA), western blot, quantitative RT-PCR and immunofluorescence.
RESULTS
IL-1β and IL-18 levels produced in sera of IFN-α non-responders were significantly lower than those of responders and normal donors. Additionally, expression of IL-1β and inflammasome components was decreased in peripheral blood mononuclear cells (PBMC) of non-responders, compared with those of responders. In vitro experiments on HepG2, HepG2.2.15 and HepAD38 cell lines showed that HBV induces a significant decrease in IL-1β production through inhibiting activation of the NF-κB signaling and inflammasome/caspase-1 pathways. And hepatitis B virus polymerase (HBV-Pol) appeared crucial for these inhibitory effects of HBV.
CONCLUSION
IL-1β production is suppressed in HBV carriers and IFN-α non-responders. HBV induces a significant decrease in IL-1β production through inhibiting the NF-κB signaling and inflammasome pathways, for which HBV-Pol is a crucial requirement. Trial approval number: 20 173 402.
Substances chimiques
Antiviral Agents
0
Gene Products, pol
0
IL18 protein, human
0
IL1B protein, human
0
Inflammasomes
0
Interferon-alpha
0
Interleukin-18
0
Interleukin-1beta
0
P protein, Hepatitis B virus
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2273-2284Informations de copyright
© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Paul N, Han SH. Combination therapy for chronic hepatitis B: current indications. Curr Hepat Rep. 2011;10:98-105.
Hadziyannis SJ, Vassilopoulos D, Hadziyannis E. The natural course of chronic hepatitis B virus infection and its management. Adv Pharmacol. 2013;67:247-291.
Franchi L, Munoz-Planillo R, Nunez G. Sensing and reacting to microbes through the inflammasomes. Nat Immunol. 2012;13:325-332.
Epstein FH, Dinarello CA. Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med. 1984;311:1413-1418.
Allen IC, Scull MA, Moore CB, et al. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity. 2009;30:556-565.
Ichinohe T, Lee HK, Ogura Y, Flavell R, Iwasaki A. Inflammasome recognition of influenza virus is essential for adaptive immune responses. J Exp Med. 2009;206:79-87.
Dombrowski Y, Peric M, Koglin S, et al. Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions. Sci Transl Med. 2011;3:82ra38.
Ona VO, Li M, Vonsattel J, et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature. 1999;399:263-267.
Li P, Allen H, Banerjee S, et al. Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell. 1995;80:401-411.
Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009;7:99-109.
Capobianchi MR, Abbate I, Cappiello G, Solmone M. HCV and interferon: viral strategies for evading innate defence mechanisms in the virus-host battle. Cell Death Differ. 2003;10(Suppl 1):S22-S24.
Negash AA, Ramos HJ, Crochet N, et al. IL-1beta production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. PLoS Pathog. 2013;9:e1003330.
Gregory SM, Davis BK, West JA, et al. Discovery of a viral NLR homolog that inhibits the inflammasome. Science. 2011;331:330-334.
Bump N, Hackett M, Hugunin M, et al. Inhibition of ICE family proteases by baculovirus antiapoptotic protein p35. Science. 1995;269:1885-1888.
Saitoh T, Fujita N, Jang MH, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008;456:264-268.
Watashi K, Liang G, Iwamoto M, et al. Interleukin-1 and tumor necrosis factor-alpha trigger restriction of hepatitis B virus infection via a cytidine deaminase activation-induced cytidine deaminase (AID). J Biol Chem. 2013;288:31715-31727.
Jegaskanda S, Ahn SH, Skinner N, et al. Downregulation of interleukin-18-mediated cell signaling and interferon gamma expression by the hepatitis B virus e antigen. J Virol. 2014;88:10412-10420.
Kimura K, Kakimi K, Wieland S, Guidotti LG, Chisari FV. Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice. J Virol. 2002;76:10702-10707.
Petrasek J, Bala S, Csak T, et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest. 2012;122:3476-3489.
Vandanmagsar B, Youm Y-H, Ravussin A, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;17:179-188.
Yu X, Lan P, Hou X, et al. HBV inhibits LPS-induced NLRP3 inflammasome activation and IL-1beta production via suppressing the NF-kappaB pathway and ROS production. J Hepatol. 2017;66:693-702.
Xiao C, Qin B, Chen L, Liu H, Zhu Y, Lu X. Preactivation of the interferon signalling in liver is correlated with nonresponse to interferon alpha therapy in patients chronically infected with hepatitis B virus. J Viral Hepat. 2012;19:e1-10.
Torre D, Zeroli C, Giola M, et al. Serum levels of interleukin-1 alpha, interleukin-1 beta, interleukin-6, and tumor necrosis factor in patients with acute viral hepatitis. Clin Infect Dis. 1994;18:194-198.
Dunn C, Brunetto M, Reynolds G, et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med. 2007;204:667-680.
Fang R, Hara H, Sakai S, et al. Type I interferon signaling regulates activation of the absent in melanoma 2 inflammasome during Streptococcus pneumoniae infection. Infect Immun. 2014;82:2310-2317.
Wang H, Mao L, Meng G. The NLRP3 inflammasome activation in human or mouse cells, sensitivity causes puzzle. Protein Cell. 2013;4:565-568.
Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117:3720-3732.
Westerterp M, Fotakis P, Ouimet M, et al. Cholesterol efflux pathways suppress inflammasome activation, NETosis and atherogenesis. Circulation. 2018;138(9):898-912.
Hornung V, Ablasser A, Charrel-Dennis M, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458:514-518.
Zhen J, Zhang L, Pan J, et al. AIM2 mediates inflammation-associated renal damage in hepatitis B virus-associated glomerulonephritis by regulating caspase-1, IL-1beta, and IL-18. Mediators Inflamm. 2014;2014:190860.
Boaru SG, Borkham-Kamphorst E, Tihaa L, Haas U, Weiskirchen R. Expression analysis of inflammasomes in experimental models of inflammatory and fibrotic liver disease. J Inflamm (Lond). 2012;9:49.
Tilg H, Moschen AR, Szabo G. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology. 2016;64:955-965.
Chen J, Yuan Z. Interplay between hepatitis B virus and the innate immune responses: implications for new therapeutic strategies. Virol Sin. 2014;29:17-24.
Cheng X, Xia Y, Serti E, et al. Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages[J]. Hepatology. 2017;66(6):1779-1793.
Verrier ER, Yim S-A, Heydmann L, et al. Hepatitis B virus evasion from cyclic guanosine monophosphate-adenosine monophosphate synthase sensing in human hepatocytes[J]. Hepatology. 2018;68(5):1695-1709.
Liu Y, Li J, Chen J, et al. Hepatitis B virus polymerase disrupts K63-linked ubiquitination of STING to block innate cytosolic DNA-sensing pathways. J Virol. 2015;89:2287-2300.
Chen J, Wu M, Zhang X, et al. Hepatitis B virus polymerase impairs interferon-alpha-induced STAT activation through inhibition of importin-alpha5 and protein kinase C-delta. Hepatology. 2013;57:470-482.
Liu D, Wu A, Cui L, et al. Hepatitis B virus polymerase suppresses NF-kappaB signaling by inhibiting the activity of IKKs via interaction with Hsp90beta. PLoS ONE. 2014;9:e91658.
Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV. Viral clearance without destruction of infected cells during acute HBV infection. Science. 1999;284:825-829.
Manigold T, Böcker U, Chen J, et al. Hepatitis B core antigen is a potent inductor of interleukin-18 in peripheral blood mononuclear cells of healthy controls and patients with hepatitis B infection. J Med Virol. 2003;71:31-40.