Increased type-I interferon level is associated with liver damage and fibrosis in primary sclerosing cholangitis.
Journal
Hepatology communications
ISSN: 2471-254X
Titre abrégé: Hepatol Commun
Pays: United States
ID NLM: 101695860
Informations de publication
Date de publication:
01 Mar 2024
01 Mar 2024
Historique:
received:
17
10
2023
accepted:
17
12
2023
medline:
15
2
2024
pubmed:
15
2
2024
entrez:
15
2
2024
Statut:
epublish
Résumé
The level of type-I interferons (IFNs) in primary sclerosing cholangitis (PSC) was investigated to evaluate its association with disease activity and progression. Bioactive type-I IFNs were evaluated in a murine model of PSC and human patients' sera using a cell-based reporter assay and ELISA techniques. In total, 57 healthy participants, 71 PSC, and 38 patients with primary biliary cholangitis were enrolled in this study. Bioactive type-I IFNs were elevated in the liver and serum of multidrug resistance protein 2-deficient animals and showed a correlation with the presence of CD45+ immune cells and serum alanine transaminase levels. Concordantly, bioactive type-I IFNs were elevated in the sera of patients with PSC as compared to healthy controls (sensitivity of 84.51%, specificity of 63.16%, and AUROC value of 0.8267). Bioactive IFNs highly correlated with alkaline phosphatase (r=0.4179, p<0.001), alanine transaminase (r=0.4704, p<0.0001), and gamma-glutamyl transpeptidase activities (r=0.6629, p<0.0001) but not with serum bilirubin. In addition, patients with PSC with advanced fibrosis demonstrated significantly higher type-I IFN values. Among the type-I IFN subtypes IFNα, β and IFNω could be detected in patients with PSC with IFNω showing the highest concentration among the subtypes and being the most abundant among patients with PSC. The selectively elevated bioactive type-I IFNs specifically the dominating IFNω could suggest a novel inflammatory pathway that might also have a hitherto unrecognized role in the pathomechanism of PSC.
Sections du résumé
BACKGROUND
BACKGROUND
The level of type-I interferons (IFNs) in primary sclerosing cholangitis (PSC) was investigated to evaluate its association with disease activity and progression.
METHODS
METHODS
Bioactive type-I IFNs were evaluated in a murine model of PSC and human patients' sera using a cell-based reporter assay and ELISA techniques. In total, 57 healthy participants, 71 PSC, and 38 patients with primary biliary cholangitis were enrolled in this study.
RESULTS
RESULTS
Bioactive type-I IFNs were elevated in the liver and serum of multidrug resistance protein 2-deficient animals and showed a correlation with the presence of CD45+ immune cells and serum alanine transaminase levels. Concordantly, bioactive type-I IFNs were elevated in the sera of patients with PSC as compared to healthy controls (sensitivity of 84.51%, specificity of 63.16%, and AUROC value of 0.8267). Bioactive IFNs highly correlated with alkaline phosphatase (r=0.4179, p<0.001), alanine transaminase (r=0.4704, p<0.0001), and gamma-glutamyl transpeptidase activities (r=0.6629, p<0.0001) but not with serum bilirubin. In addition, patients with PSC with advanced fibrosis demonstrated significantly higher type-I IFN values. Among the type-I IFN subtypes IFNα, β and IFNω could be detected in patients with PSC with IFNω showing the highest concentration among the subtypes and being the most abundant among patients with PSC.
CONCLUSIONS
CONCLUSIONS
The selectively elevated bioactive type-I IFNs specifically the dominating IFNω could suggest a novel inflammatory pathway that might also have a hitherto unrecognized role in the pathomechanism of PSC.
Identifiants
pubmed: 38358371
doi: 10.1097/HC9.0000000000000380
pii: 02009842-202403010-00005
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.
Références
Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis—A comprehensive review. J Hepatol. 2017;67:1298–1323.
Lazaridis KN, LaRusso NF. Primary sclerosing cholangitis. N Engl J Med. 2016;375:2501–2502.
Jones DE. Pathogenesis of primary biliary cirrhosis. J Hepatol. 2003;39:639–648.
Lazaridis KN, LaRusso NF. Primary sclerosing cholangitis. N Engl J Med. 2016;375:1161–1170.
Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Lancet. 2018;391:2547–2559.
Ravichandran G, Neumann K, Berkhout LK, Weidemann S, Langeneckert AE, Schwinge D, et al. Interferon-gamma-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice. J Hepatol. 2019;71:773–782.
Dold L, Frank L, Lutz P, Kaczmarek DJ, Kramer B, Nattermann J, et al. Il-6-dependent Stat3 activation and induction of proinflammatory cytokines in primary sclerosing cholangitis. Clin Transl Gastroenterol. 2023;14:e00603.
Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol. 2005;5:375–386.
Crouse J, Kalinke U, Oxenius A. Regulation of antiviral T cell responses by type I interferons. Nat Rev Immunol. 2015;15:231–242.
Petrasek J, Dolganiuc A, Csak T, Kurt-Jones EA, Szabo G. Type I interferons protect from Toll-like receptor 9-associated liver injury and regulate IL-1 receptor antagonist in mice. Gastroenterology. 2011;140:697–708 e694.
Zhai Y, Qiao B, Gao F, Shen X, Vardanian A, Busuttil RW, et al. Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion. Hepatology. 2008;47:199–206.
Ghazarian M, Revelo XS, Nohr MK, Luck H, Zeng K, Lei H, et al. Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome. Sci Immunol. 2017;2:eaai7616.
Bae HR, Hodge DL, Yang GX, Leung PSC, Chodisetti SB, Valencia JC, et al. The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity. Hepatology. 2018;67:1408–1419.
Takii Y, Nakamura M, Ito M, Yokoyama T, Komori A, Shimizu-Yoshida Y, et al. Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis. Lab Invest. 2005;85:908–920.
Colonna M. TLR pathways and IFN-regulatory factors: To each its own. Eur J Immunol. 2007;37:306–309.
Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, et al. American Association for the Study of Liver D. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51:660–678.
European Association for the Study of the L. EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. J Hepatol. 2009;51:237–267.
Eckert C, Kim YO, Julich H, Heier EC, Klein N, Krause E, et al. Podoplanin discriminates distinct stromal cell populations and a novel progenitor subset in the liver. Am J Physiol Gastrointest Liver Physiol. 2016;310:G1–G12.
Heier EC, Meier A, Julich-Haertel H, Djudjaj S, Rau M, Tschernig T, et al. Murine CD103+ dendritic cells protect against steatosis progression towards steatohepatitis. J Hepatol. 2017;66:1241–1250.
Julich-Haertel H, Tiwari M, Mehrfeld C, Krause E, Kornek M, Lukacs-Kornek V. Isolation and enrichment of liver progenitor subsets identified by a novel surface marker combination. J Vis Exp. 2017;120:55284.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–408.
Fickert P, Pollheimer MJ, Beuers U, Lackner C, Hirschfield G, Housset C, et al. Characterization of animal models for primary sclerosing cholangitis (PSC). J Hepatol. 2014;60:1290–1303.
Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H, et al. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology. 2004;127:261–274.
Coulstock E, Sosabowski J, Ovecka M, Prince R, Goodall L, Mudd C, et al. Liver-targeting of interferon-alpha with tissue-specific domain antibodies. PLoS One. 2013;8:e57263.
Kita H, Lian ZX, Van de Water J, He XS, Matsumura S, Kaplan M, et al. Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells. J Exp Med. 2002;195:113–123.
Matsumura S, Kita H, He XS, Ansari AA, Lian ZX, Van De Water J, et al. Comprehensive mapping of HLA-A0201-restricted CD8 T-cell epitopes on PDC-E2 in primary biliary cirrhosis. Hepatology. 2002;36:1125–1134.
Jones DE. Autoantigens in primary biliary cirrhosis. J Clin Pathol. 2000;53:813–821.
Bae HR, Leung PS, Tsuneyama K, Valencia JC, Hodge DL, Kim S, et al. Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. Hepatology. 2016;64:1189–1201.
de Vries EM, Wang J, Leeflang MM, Boonstra K, Weersma RK, Beuers UH, et al. Alkaline phosphatase at diagnosis of primary sclerosing cholangitis and 1 year later: Evaluation of prognostic value. Liver Int. 2016;36:1867–1875.
Blanco-Grau A, Gabriel-Medina P, Rodriguez-Algarra F, Villena Y, Lopez-Martinez R, Augustin S, et al. Assessing liver fibrosis using the FIB4 index in the community setting. Diagnostics (Basel). 2021;11:2236.
Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–1325.
Corpechot C, Gaouar F, El Naggar A, Kemgang A, Wendum D, Poupon R, et al. Baseline values and changes in liver stiffness measured by transient elastography are associated with severity of fibrosis and outcomes of patients with primary sclerosing cholangitis. Gastroenterology. 2014;146:970–979; quiz e915–e976.
Singh S, Fujii LL, Murad MH, Wang Z, Asrani SK, Ehman RL, et al. Liver stiffness is associated with risk of decompensation, liver cancer, and death in patients with chronic liver diseases: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2013;11:1573–1584 e1571-1572; quiz e1588–e1579.
Schmechel S, Konrad A, Diegelmann J, Glas J, Wetzke M, Paschos E, et al. Linking genetic susceptibility to Crohn’s disease with Th17 cell function: IL-22 serum levels are increased in Crohn’s disease and correlate with disease activity and IL23R genotype status. Inflamm Bowel Dis. 2008;14:204–212.
Ganguly D. Do type I interferons link systemic autoimmunities and metabolic syndrome in a pathogenetic continuum? Trends Immunol. 2018;39:28–43.
Weber F. Interaction of hepatitis C virus with the type I interferon system. World J Gastroenterol. 2007;13:4818–4823.
Halaoui AF, Ali AH, Habib SG, Kanso M, Daniel F, Mukherji DM, et al. Gender differences in liver fibrosis among patients younger than 50 years: A retrospective cohort study. Clin Res Hepatol Gastroenterol. 2020;44:733–738.
Xiong M, Li J, Yang S, Zeng F, Ji Y, Liu J, et al. Influence of gender and reproductive factors on liver fibrosis in patients with chronic hepatitis B infection. Clin Transl Gastroenterol. 2019;10:e00085.
Muriel P. Alpha-interferon prevents liver collagen deposition and damage induced by prolonged bile duct obstruction in the rat. J Hepatol. 1996;24:614–621.
Serejo F, Costa A, Oliveira AG, Ramalho F, Batista A, De Moura MC. Alpha-interferon improves liver fibrosis in chronic hepatitis C: Clinical significance of the serum N-terminal propeptide of procollagen type III. Dig Dis Sci. 2001;46:1684–1689.
Tanabe J, Izawa A, Takemi N, Miyauchi Y, Torii Y, Tsuchiyama H, et al. Interferon-beta reduces the mouse liver fibrosis induced by repeated administration of concanavalin A via the direct and indirect effects. Immunology. 2007;122:562–570.
Li SF, Zhao FR, Shao JJ, Xie YL, Chang HY, Zhang YG. Interferon-omega: Current status in clinical applications. Int Immunopharmacol. 2017;52:253–260.
Pujantell M, Altfeld M. Consequences of sex differences in Type I IFN responses for the regulation of antiviral immunity. Front Immunol. 2022;13:986840.
Swiecki M, Colonna M. The multifaceted biology of plasmacytoid dendritic cells. Nat Rev Immunol. 2015;15:471–485.
Maroni L, Haibo B, Ray D, Zhou T, Wan Y, Meng F, et al. Functional and structural features of cholangiocytes in health and disease. Cell Mol Gastroenterol Hepatol. 2015;1:368–380.
Vesterhus M, Holm A, Hov JR, Nygard S, Schrumpf E, Melum E, et al. Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis. J Hepatol. 2017;66:1214–1222.
Palmela C, Peerani F, Castaneda D, Torres J, Itzkowitz SH. Inflammatory bowel disease and primary sclerosing cholangitis: A review of the phenotype and associated specific features. Gut Liver. 2018;12:17–29.
Sorensen JO, Nielsen OH, Andersson M, Ainsworth MA, Ytting H, Belard E, et al. Inflammatory bowel disease with primary sclerosing cholangitis: A Danish population-based cohort study 1977-2011. Liver Int. 2018;38:532–541.
Kole A, He J, Rivollier A, Silveira DD, Kitamura K, Maloy KJ, et al. IFNs regulate effector and regulatory T cell accumulation and anti-inflammatory cytokine production during T cell-mediated colitis. J Immunol. 2013;191:2771–2779.
Giles EM, Sanders TJ, McCarthy NE, Lung J, Pathak M, MacDonald TT, et al. Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease. Mucosal Immunol. 2017;10:184–193.
Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY, Keller BC, et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell. 2015;160:447–460.