Interferon-β Mediates Signaling Pathways Uniquely Regulated in Hepatic Stellate Cells and Attenuates the Progression of Hepatic Fibrosis in a Dietary Mouse Model

Shimozono, Rieko; Nishimura, Kazumi; Akiyama, Hideo; Funamoto, Satoru; Izawa, Akiko; Sai, Takafumi; Kunita, Kana; Kainoh, Mie; Suzuki, Tomohiko; Kawada, Norifumi

doi:10.1089/jir.2014.0096

Cited by 13 publications

(11 citation statements)

References 30 publications

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“…38 In addition, IFNb significantly reduced liver fibrosis with accompanying reduced expression levels of TLR4 adaptor molecule MyD88. 39 IFNAR1-lacking mice also showed significantly increased susceptibility to hepatotoxin-or cholestasisinduced liver fibrosis. 18 Furthermore, the hepatoprotective type 1 IFN-IL1RN axis has been well documented in several types of liver injuries, such as RNA-and DNA-induced liver injury associated with TLR3 and TLR9, respectively.…”

Section: Tlr5-ifnb-il1ra Modulates Liver Fibrosismentioning

confidence: 97%

Toll-Like Receptor 5 Signaling Ameliorates Liver Fibrosis by Inducing Interferon β–Modulated IL-1 Receptor Antagonist in Mice

Zhou

Kim

et al. 2020

The American Journal of Pathology

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Bacterial flagellin, recognized by cell surface of Toll-like receptor (TLR) 5, is a potent activator of many types of cells, leading to the activation of innate or adaptive immunity, which are pivotal in regulating fibrotic process. However, the exact role of TLR5 signaling in hepatic fibrogenesis remains unclear, and this study aims to elucidate its underlying mechanisms. Flagellin was injected to hepatotoxin-and cholestasis-induced liver fibrosis murine models. Flagellin-induced TLR5 activation significantly decreased the severity of liver fibrosis. Interestingly, the expression levels of IL-1 receptor antagonist (IL1RN) and interferon (IFN)b markedly increased in fibrotic livers on flagellin treatment. Consistently, in vivo activation of TLR5 signaling markedly increased IFNb and IL1RN expression in the livers. Notably, flagellin injection significantly exacerbated the severity of liver fibrosis in IFN-a/b receptor 1 (IFNAR1) knockout mice. Furthermore, hepatic expression of IL1RN in the fibrotic livers of IFNAR1 knockout mice was significantly lower than those of wild-type mice. In support of these findings, flagellin-mediated IL1RN production is not sufficient to alleviate the severity of hepatic fibroinflammatory responses in IFNAR1-deficient milieu. Finally, hepatic stellate cells treated with IL1RN had significantly decreased cellular activation and its associated fibrogenic responses. Collectively, manipulation of TLR5 signaling may be a promising therapeutic strategy for the treatment of liver fibrosis.

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Section: Tlr5-ifnb-il1ra Modulates Liver Fibrosismentioning

confidence: 97%

Toll-Like Receptor 5 Signaling Ameliorates Liver Fibrosis by Inducing Interferon β–Modulated IL-1 Receptor Antagonist in Mice

Zhou

Kim

et al. 2020

The American Journal of Pathology

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“…The severity of hepatic in ammation has been identi ed as an independent risk factor for brosis progression in NASH [49]. Interferon b (IFNb) was suggested as a potential anti-brotic for NASH with its ability to downregulate brogenic genes associated with TGFb-1 and MyD88 pathways [15]. As such, we measured total gene expression of IFNb in the livers of NASH mice, whereupon we observed that a single dose of hAECs signi cantly increased IFNb where a double dose of hAECs failed to achieve this.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, anti-oxidants, including N-Acetylcysteine (NAC) and S-adenosylmethionine (SAMe), have been explored as potential treatment for NASH [11][12][13] since oxidative stress has been implicated in the progression of the LPC response [14] and pathogenesis of NASH. Recent pre-clinical studies have also explored interferon b (IFNb) as a potential anti-brotic for NASH, with its ability to downregulate brogenic genes associated with TGFb-1 and MyD88 pathways [15]. While these emerging treatments have shown varying degrees of success, there remains an urgent need to develop e cacious therapies that address the complex pathophysiologic processes implicated in NASH.…”

Section: Introductionmentioning

confidence: 99%

Addressing the Liver Progenitor Cell Response and Hepatic Oxidative Stress in Experimental Non-alcoholic Fatty Liver Disease/non-alcoholic Steatohepatitis Using Amniotic Epithelial Cells

Goonetilleke

Kuk

Correia

et al. 2020

Preprint

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Background: Non-alcoholic steatohepatitis (NASH) is the most common liver disease globally and can progress to cirrhosis and hepatocellular carcinoma (HCC). Currently, patient education and lifestyle changes are the major tools to prevent the continuous progression of NASH. Emerging therapies in NASH target known pathological processes involved in the progression of the disease including inflammation, fibrosis, oxidative stress and apoptosis. Human amniotic epithelial cells (hAECs) were previously shown to be beneficial in experimental models of chronic liver injury, reducing hepatic inflammation and fibrosis. Previous studies have shown that the interaction between liver progenitor cells (LPCs) plays a significant role in the development of fibrosis and HCC in mouse models of fatty liver disease. In this study, we examined the effect hAECs have on the LPC response and hepatic oxidative stress in an experimental model of NASH.Methods: Experimental NASH was induced in C57BL/6J male mice using a high-fat, high fructose diet for 42 weeks. Mice received either a single intraperitoneal injection of 2 × 106 hAECs at week 34 or an additional hAEC dose at week 38. Changes to the LPC response and oxidative stress regulators were measured.Results: hAEC administration significantly reduced the expansion of LPCs and their mitogens, IL-6, IFNγ and TWEAK. hAEC administration also reduced neutrophil infiltration and myeloperoxidase production with a concurrent increase in heme oxygenase-1 production. These observations were accompanied by a significant increase in total levels of anti-fibrotic IFNb in mice treated with a single dose of hAECs, which appeared to be independent of c-GAS-STING activation.Conclusions: Expansion of liver progenitor cells, hepatic inflammation and oxidative stress associated with experimental NASH were attenuated by hAEC administration. Given that repeated doses did not significantly increase efficacy, future studies assessing the impact of dose escalation and/or timing of dose may provide insights into clinical translation.

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“…Consistent with the latter finding, MyD88 mRNA expression was increased in monocytes of chronic HCV infected patients [ 36 ]. In experimental animal models, attenuation of either liver fibrosis or liver inflammation was associated by reduced MyD88 expression in either nonalcoholic steatohepatitis related hepatic fibrosis [ 45 ] or chronic alcohol fed rats [ 46 ] respectively. Zhang study [ 47 ] revealed increased MyD88 mRNA expression in HBV-transgenic mice having non-alcoholic fatty liver disease as well as in HepG2.2.15 cells treated with stearic acid to induce steatosis.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Dysregulation of Upstream Signaling of IFN Pathway in Chronic HCV Type 4 Induced Liver Fibrosis

et al. 2016

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IFN orchestrates the expression of various genes to halt hepatitis C virus (HCV) replication with the possibility of either reduced or increased liver fibrosis; due to controlled viral replication or overproduction of inflammatory mediators, repectively. In this study, we examined the transcriptional profiling of type I IFN related genes in HCV-chronically infected patients with varying degrees of liver fibrosis. PCR array was used to examine the expression of 84 type I IFN related genes in peripheral blood mononuclear cells (PBMCs) RNA from 12 treatment-naïve chronic HCV patients (5 F0-F1 and 7 F2-F4) and 5 healthy subjects. We further validated our results by quantitative real time PCR (qRT-PCR) in 103 treatment-naïve chronic HCV patients (43 F0-F1 and 60 F2-F4) and 15 controls. PCR array data revealed dysregulation in TLR7 pathway. The expression of TLR7 was decreased by 4 folds and MyD88 was increased by 3 folds in PBMCs of F2-F4 patients when compared to the healthy volunteers (p = 0.03 and 0.002, respectively). In addition, IRF7 and TLR7 showed dramatic downregulation (6 and 8 folds, respectively) in F2-F4 patients when compared to F0-F1 ones. qRT-PCR confirmed the altered expression patterns of TLR7 and MyD88 in F2-F4 patients when compared to either controls or F0-F1 patients. However, by qRT-PCR, IRF7 and NF-κB1 (TLR7 pathway transcription factors) exhibited similar mRNA abundance among F2-F4 and F0-F1 patients. These results suggest that TLR7 and MyD88 are possible candidates as biomarkers for the progression of HCV-induced liver fibrosis and/ or targets for therapeutic intervention.

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Interferon-β Mediates Signaling Pathways Uniquely Regulated in Hepatic Stellate Cells and Attenuates the Progression of Hepatic Fibrosis in a Dietary Mouse Model

Cited by 13 publications

References 30 publications

Toll-Like Receptor 5 Signaling Ameliorates Liver Fibrosis by Inducing Interferon β–Modulated IL-1 Receptor Antagonist in Mice

Toll-Like Receptor 5 Signaling Ameliorates Liver Fibrosis by Inducing Interferon β–Modulated IL-1 Receptor Antagonist in Mice

Addressing the Liver Progenitor Cell Response and Hepatic Oxidative Stress in Experimental Non-alcoholic Fatty Liver Disease/non-alcoholic Steatohepatitis Using Amniotic Epithelial Cells

Transcriptional Dysregulation of Upstream Signaling of IFN Pathway in Chronic HCV Type 4 Induced Liver Fibrosis

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