IL-17 Imbalance Promotes the Pyroptosis in Immune-Mediated Liver Injury Through STAT3-IFI16 Axis
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Autoimmune hepatitis (AIH) affects all age group and occurs mainly in women. Pyroptosis is a novel programmed cell death featured with cell bursting and release of proinflammatory cytokines. A deeper understanding of AIH pathogenesis will contribute to novel therapy for AIH patients. Here, we aimed to investigate the role of IL-17 in immune-mediated liver injury. The levels of cytokines were measured by ELISA, and mRNA levels of STAT3 and IFN gamma-inducible protein 16 (IFI16) were detected by PCR. Expressions of STAT3, IFI16, gasdermin D and cleaved caspase-1 were measured by western-blotting. Immunohistochemical staining and transmission electron microscopy were applied to evaluate liver histopathological changes of the treated mice. Our results showed that the levels of IFI16 was increased in hepatocytes treated with IL-17 protein, and further elevated after STAT3-overexpressed (STAT3-OE) lentivirus treatment. The levels of IFI16 were reduced in hepatocytes treated with IL-17 neutralizing Ab (nAb), but were significantly increased after STAT3-OE treatment. Pyroptosis was observed in hepatocytes treated with IL-17 protein, and further cell damage was observed after STAT3-OE lentivirus treatment. Liver damage was alleviated in mice treated with IL-17 nAb, however sever damage was experienced after STAT3-OE lentivirus treatment. A binding interaction between IFI16 and STAT3 was detected in IL-17 treated hepatocytes. Glutathione transaminase activity was enhanced in concanavalin A-induced AIH mice compared to the control group (p<0.01). IL-17 plays an important role in activating STAT3 and up-regulating IFI16, which may promote the pyroptosis in AIH-related liver injury through STAT3-IFI16 axis.
Abstract
Autoimmune hepatitis (AIH) affects all age group and occurs mainly in women. Pyroptosis is a novel programmed cell death featured with cell bursting and release of proinflammatory cytokines. A deeper understanding of AIH pathogenesis will contribute to novel therapy for AIH patients. Here, we aimed to investigate the role of IL-17 in immune-mediated liver injury. The levels of cytokines were measured by ELISA, and mRNA levels of STAT3 and IFN gamma-inducible protein 16 (IFI16) were detected by PCR. Expressions of STAT3, IFI16, gasdermin D and cleaved caspase-1 were measured by western-blotting. Immunohistochemical staining and transmission electron microscopy were applied to evaluate liver histopathological changes of the treated mice. Our results showed that the levels of IFI16 was increased in hepatocytes treated with IL-17 protein, and further elevated after STAT3-overexpressed (STAT3-OE) lentivirus treatment. The levels of IFI16 were reduced in hepatocytes treated with IL-17 neutralizing Ab (nAb), but were significantly increased after STAT3-OE treatment. Pyroptosis was observed in hepatocytes treated with IL-17 protein, and further cell damage was observed after STAT3-OE lentivirus treatment. Liver damage was alleviated in mice treated with IL-17 nAb, however sever damage was experienced after STAT3-OE lentivirus treatment. A binding interaction between IFI16 and STAT3 was detected in IL-17 treated hepatocytes. Glutathione transaminase activity was enhanced in concanavalin A-induced AIH mice compared to the control group (p<0.01). IL-17 plays an important role in activating STAT3 and up-regulating IFI16, which may promote the pyroptosis in AIH-related liver injury through STAT3-IFI16 axis.
참고문헌 (29)
- Siegel RL, "Cancer statistics, 2022", CA Cancer J Clin, 72, pp.7~33 (2022)
- Llovet JM, "Hepatocellular carcinoma", Nat Rev Dis Primers, 7, pp.6~ (2021)
- Fujiwara N, "Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine", J Hepatol, 68, pp.526~549 (2018)
- Sharma R, "Cancer risk in patients with autoimmune hepatitis : a nationwide population-based cohort study with histopathology", Am J Epidemiol, 191, pp.298~319 (2022)
- Doherty DG, "Immunity, tolerance and autoimmunity in the liver : a comprehensive review", J Autoimmun, 66, pp.60~75 (2016)
- Horst AK, "Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells", Cell Mol Immunol, 13, pp.277~292 (2016)
- Dos Santos IP, "Patients with treated autoimmune hepatitis and persistent suppression of plasmacytoid dendritic cells: a different point of view"
- "Autoimmune hepatitis", Nat Rev Dis Primers, 4, pp.18018~ (2018)
- Rigopoulou EI, "Current trends and characteristics of hepatocellular carcinoma in patients with autoimmune liver diseases", Cancers(Basel), 13, pp.102~ (2021)
- Mack CL, "Diagnosis and management of autoimmune hepatitis in adults and children : 2019 practice guidance and guidelines from the American Association for the Study of Liver Diseases", Hepatology, 72, pp.671~722 (2020)
- European Association for the Study of the Liver, "EASL clinical practice guidelines : autoimmune hepatitis", J Hepatol, 63, pp.971~1004 (2015)
- Dalekos GN, "First results from a propensity matching trial of mycophenolate mofetil vs. azathioprine in treatmentnaive AIH patients", Front Immunol, 12, pp.798602~ (2022)
- Lohse AW, "Second-line and third-line therapy for autoimmune hepatitis : a position statement from the European Reference Network on Hepatological Diseases and the International Autoimmune Hepatitis Group", J Hepatol, 73, pp.1496~1506 (2020)
- Ikeda A, "Progression of autoimmune hepatitis is mediated by IL-18-producing dendritic cells and hepatic CXCL9 expression in mice", Hepatology, 60, pp.224~236 (2014)
- Zhao R, "A critical role for interleukin-1β in the progression of autoimmune diseases", Int Immunopharmacol, 17, pp.658~669 (2013)
- Zhao L, "Interleukin-17contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6expression", PLoS One, 6, pp.e18909~ (2011)
- Nakayama S, "Autoimmune hepatitis triggered by anti-TNF-α therapy", Case Rep Med, 2013, pp.561748~ (2013)
- Jaruga B, "IFN-gamma", STAT1 acts as a proinflammatory signal in T cellmediated hepatitis via induction of multiple chemokines and adhesion molecules : a critical role of IRF-1, 2004, pp.287, G1044~G1052
- Hammerich L, "Role of IL-17 and Th17 cells in liver diseases", Clin Dev Immunol, 2011, pp.345803~ (2011)
- Singh B, "Modulation of autoimmune diseases by interleukin(IL)-17 producing regulatory T helper(Th17)cells", Indian J Med Res, 138, pp.591~594 (2013)
- Beringer A, "IL-17 and IL-17-producing cells and liver diseases, with focus on autoimmune liver diseases", Autoimmun Rev, 17, pp.1176~1185 (2018)
- Lorenzini T, "STAT mutations as program switchers : turning primary immunodeficiencies into autoimmune diseases", J Leukoc Biol, 101, pp.29~38 (2017)
- Yasumi Y, "Interleukin-17 as a new marker of severity of acute hepatic injury", Hepatol Res, 37, pp.248~254 (2007)
- Yu H, "IL-17 contributes to autoimmune hepatitis", J Huazhong Univ Sci Technolog Med Sci, 30, pp.443~446 (2010)
- Liu X, "Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores", Nature, 535, pp.153~158 (2016)
- Lei L, "Interleukin-17 induces pyroptosis in osteoblasts through the NLRP3 inflammasome pathway in vitro", Int Immunopharmacol, 96, pp.107781~ (2021)
- Caneparo V, "Anti-IFI16 antibodies and their relation to disease characteristics in systemic lupus erythematosus", Lupus, 22, pp.607~613 (2013)
- De Andrea M, "Serum IFI16 and anti-IFI16 antibodies in psoriatic arthritis", Clin Exp Immunol, 199, pp.88~96 (2020)
- Matsuda T, "Signal transducer and activator of transcription 3 regulation by novel binding partners", World J Biol Chem, 6, pp.324~332 (2015)