Transforming growth factor β latency: A mechanism of cytokine storage and signalling regulation in liver homeostasis and disease

Li, Yujia; Fan, Wendy; Link, Frederik; Wang, Qianqian; Dooley, Steven

doi:10.1016/j.jhepr.2021.100397

Cited by 41 publications

(34 citation statements)

References 200 publications

(438 reference statements)

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“…Fibrosis is common to late stages of NAFLD, and if allowed to progress can lead to cirrhosis and loss of liver function [ 5 ]. Fibrosis is typically initiated by the release of pro-fibrotic cytokines such as TGFβ from several cell types including injured hepatocytes, resident immune cells, and infiltrating immune cells [ [6] , [7] , [8] , [9] , [10] ]. These cytokines activate hepatic stellate cells and infiltrating bone marrow-derived stem cells in the liver sinusoids, where they deposit extracellular matrix proteins leading to fibrosis [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Sphingosine kinase 1 mediates sexual dimorphism in fibrosis in a mouse model of NASH

Montefusco

Jamil

Maczis

et al. 2022

Molecular Metabolism

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Section: Introductionmentioning

confidence: 99%

Sphingosine kinase 1 mediates sexual dimorphism in fibrosis in a mouse model of NASH

Montefusco

Jamil

Maczis

et al. 2022

Molecular Metabolism

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“…High HBV DNA load, and high HBeAg and HBsAg levels may inhibit the immune cell function of patients, leading to the reduction of Flt-3L, IFN-g, IL-17A, and other cytokines with virus clearance effect (8,13,(22)(23)(24), and to the increase in the level of the most important cytokine for immunosuppression (IL-10) and other cytokines with immunosuppressive effect such as TGF-b1 (8,13,(25)(26)(27). In this study, compared with the incomplete virus response group, the complete virus response group had lower HBV DNA load, lower HBeAg and HBsAg levels, lower IL-10 level, and lower TGF-b level, which indicate that patients with complete virus response may have better immune clearance ability against virus.…”

Section: Discussionmentioning

confidence: 99%

Dynamic changes of cytokine profiles and virological markers during 48 weeks of entecavir treatment for HBeAg-positive chronic hepatitis B

Gao²,

Yang³

et al. 2022

Front. Immunol.

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ObjectiveThe aims of this study were to investigate the kinetic changes of serum, virological, and immunological markers during entecavir (ETV) antiviral therapy and to explore whether these indicators can predict the antiviral efficacy of ETV in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients.MethodsHBeAg-positive CHB patients were enrolled and treated with ETV 0.5 mg/day. Clinical biochemical, virological, and serological tests were performed at baseline and every 12 weeks during the 48-week treatment. Plasma levels of cytokines (Flt-3L, IFN-α2, IFN-γ, IL-10, IL-17A, IL-6, TGF-β1, TGF-β2, TGF-β3, and TNF-α) were measured at baseline and at 12 and 24 weeks after treatment. Analysis of the trends of these clinical indicators in ETV antiviral therapy was performed.ResultsA total of 105 HBeAg-positive CHB patients were enrolled, and 100 of them completed 48 weeks of ETV treatment and follow-up. After 48 weeks of treatment, hepatitis B s antigen (HBsAg) decline ≥ 1 log10 was found in seven patients, but no patient achieved HBsAg disappearance. serological HBeAg disappeared in 13 patients, and serological HBeAg transformed in 3 patients. The baseline HBsAg and HBeAg levels, HBV DNA load, IL-10, and TGF-β1 levels in the complete virological response group were lower than those in the incomplete virological response group, while the ALT level in the complete virological response group was higher than that in the incomplete virological response group. Both univariate analysis and multivariate analysis showed that baseline biochemical indexes, virological indexes, and cytokine levels had no correlation with the complete virological response at 48 weeks. In multivariate analysis, low baseline HBV DNA load, and HBeAg and IL-10 levels were significantly associated with ALT normalization after 48 weeks of ETV treatment (HBeAg OR = 1.003, 95% CI 1.001–1.006, p = 0.007; HBV DNA OR = 0.184, 95% CI 0.046–0.739, p = 0.017; IL-10 OR = 0.040, 95% CI 0.972–0.999, p = 0.040).ConclusionCytokine levels changed dynamically during ETV antiviral therapy. Low baseline HBV DNA load, and HBeAg and IL-10 levels were significantly associated with ALT normalization after 48 weeks of ETV treatment.

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“…TGFβ1 is tightly regulated in a spatial manner. It is secreted in an inactive state bound to latent TGFβ binding proteins in the extracellular matrix 49 . The localization of TGFβ1 in the ECM allows for rapid mobilization in response to cellular stimuli and activation of TGFβ1.…”

Section: Discussionmentioning

confidence: 99%

Secreted folate receptor-gamma drives fibrogenesis in nonalcoholic steatohepatitis by amplifying TGFβ signaling in hepatic stellate cells

Merali

Quinn

Merali

et al. 2022

Preprint

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Hepatic fibrosis is the primary determinant of mortality in nonalcoholic steatohepatitis (NASH) patients. Antagonism of transforming growth factor β (TGFβ), a master profibrogenic cytokine, is a promising therapeutic target that has not yet been translated into an effective therapy, due in part to the lack of animal models resembling the human phenotype of NASH. Here we have identified that soluble secreted folate receptor gamma (FOLR3), expressed in humans but not rodents, is a secreted protein that is elevated in livers of NASH subjects but not in subjects with nonalcoholic fatty liver, type II diabetes, or healthy subjects. FOLR3, based on global proteomics, was the most highly expressed NASH-specific protein and positively correlated with increasing fibrosis stages, suggesting an impact on activated hepatic stellate cells (HSCs), the key fibrogenic cell in the liver. Exposure of stellate cells to exogenous FOLR3 led to elevated extracellular matrix (ECM) protein production, an effect synergistic with TGFβ1. Structurally, FOLR3 interacts with serine protease HTRA1, which downregulates TGFβ signaling through the degradation of its receptor TGFBR2. Administration of human FOLR3 to mice induced severe bridging fibrosis and an ECM pattern resembling human NASH. Our study uncovers a novel role of FOLR3 in enhancing fibrosis and identifies FOLR3 as a potential therapeutic target in NASH fibrosis.

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Transforming growth factor β latency: A mechanism of cytokine storage and signalling regulation in liver homeostasis and disease

Cited by 41 publications

References 200 publications

Sphingosine kinase 1 mediates sexual dimorphism in fibrosis in a mouse model of NASH

Sphingosine kinase 1 mediates sexual dimorphism in fibrosis in a mouse model of NASH

Dynamic changes of cytokine profiles and virological markers during 48 weeks of entecavir treatment for HBeAg-positive chronic hepatitis B

Secreted folate receptor-gamma drives fibrogenesis in nonalcoholic steatohepatitis by amplifying TGFβ signaling in hepatic stellate cells

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