Stat3 signaling activation crosslinking of TGF-β1 in hepatic stellate cell exacerbates liver injury and fibrosis

Xu, Ming-Yi; Hu, Junjie; Shen, Jie; Wang, Meiling; Zhang, Qingqing; Qu, Ying; Lu, Lungen

doi:10.1016/j.bbadis.2014.07.025

Cited by 72 publications

(83 citation statements)

References 21 publications

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“…Interestingly, these opposing outcomes were both found to be STAT3 dependent, suggesting a context-dependent component of the STAT3 effect. These observations are supported by numerous other studies that clearly establish the anti-apoptotic role of STAT3 in fibrosis [52,187,188]. …”

Section: Stat3 and Fibrosissupporting

confidence: 85%

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

Kasembeli

Bharadwaj

Robinson

et al. 2018

IJMS

137

119

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Signal transducer and activator of transcription (STAT) 3 plays a central role in the host response to injury. It is activated rapidly within cells by many cytokines, most notably those in the IL-6 family, leading to pro-proliferative and pro-survival programs that assist the host in regaining homeostasis. With persistent activation, however, chronic inflammation and fibrosis ensue, leading to a number of debilitating diseases. This review summarizes advances in our understanding of the role of STAT3 and its targeting in diseases marked by chronic inflammation and/or fibrosis with a focus on those with the largest unmet medical need.

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Section: Stat3 and Fibrosissupporting

confidence: 85%

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

Kasembeli

Bharadwaj

Robinson

et al. 2018

IJMS

137

119

View full text Add to dashboard Cite

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“…We observed higher TGF-␤1 expression in primary human hepatic stellate cells exposed to HCV-exo than in mock-treated cells. STAT3-dependent TGF-␤1 expression has been reported to play an important role in the activation and antiapoptotic effect of HSC in liver tissues of chronic hepatitis B patients and diethylinitrosamine-induced liver fibrosis in a rat model (32). Further, STAT3 is involved in modulating CTGF production upon TGF-␤ treatment in activated HSC (33).…”

Section: Discussionmentioning

confidence: 99%

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Devhare

Sasaki

Shrivastava

et al. 2017

J Virol

145

157

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Fibrogenic pathways in the liver are principally regulated by activation of hepatic stellate cells (HSC). Fibrosis is associated with chronic hepatitis C virus (HCV) infection, although the mechanism is poorly understood. HSC comprise the major population of nonparenchymal cells in the liver. Since HCV does not replicate in HSC, we hypothesized that exosomes secreted from HCV-infected hepatocytes activate HSC. Primary or immortalized human hepatic stellate (LX2) cells were exposed to exosomes derived from HCV-infected hepatocytes (HCV-exo), and the expression of fibrosis-related genes was examined. Our results demonstrated that HCV-exo internalized to HSC and increased the expression of profibrotic markers. Further analysis suggested that HCV-exo carry miR-19a and target SOCS3 in HSC, which in turn activates the STAT3-mediated transforming growth factor ␤ (TGF-␤) signaling pathway and enhances fibrosis marker genes. The higher expression of miR-19a in exosomes was also observed from HCV-infected hepatocytes and in sera of chronic HCV patients with fibrosis compared to healthy volunteers and non-HCV-related liver disease patients with fibrosis. Together, our results demonstrated that miR-19a carried through the exosomes from HCV-infected hepatocytes activates HSC by modulating the SOCS-STAT3 axis. Our results implicated a novel mechanism of exosome-mediated intercellular communication in the activation of HSC for liver fibrosis in HCV infection.IMPORTANCE HCV-associated liver fibrosis is a critical step for end-stage liver disease progression. However, the molecular mechanisms for hepatic stellate-cell activation by HCV-infected hepatocytes are underexplored. Here, we provide a role for miR-19a carried through the exosomes in intercellular communication between HCVinfected hepatocytes and HSC in fibrogenic activation. Furthermore, we demonstrate the role of exosomal miR-19a in activation of the STAT3-TGF-␤ pathway in HSC. This study contributes to the understanding of intercellular communication in the pathogenesis of liver disease during HCV infection. KEYWORDS hepatitis C virus, exosomes, miRNAs, liver fibrosis, hepatic stellate cells, microRNA H epatitis C virus (HCV) is a positive-sense, single-stranded RNA virus with a genome size of 9.6 kb that encodes several structural and nonstructural proteins. About 170 million people are infected with HCV worldwide. Chronic HCV infection often results in the development of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCVassociated liver fibrosis is a key pathological process leading to liver cirrhosis and HCC (1, 2), although the underlying mechanisms of disease progression remain unclear. Hepatic stellate cells (HSC) are involved in the pathogenesis of liver fibrosis (3). Liver injury is characterized by a phenotypic and functional transformation of normally

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“…TGF-␤ has been shown to potentiate IL-6-induced STAT3 activation in hepatoma cells (14) and activate STAT3 in hepatocytes and HSC cells (24,25). Moreover, elevated STAT3 phosphorylation was reported in fibrosis and cirrhosis patient samples in conjunction with TGF-␤ and SMAD3 activation (24,26). However, these cases of STAT3 activation were observed hours after TGF-␤ stimulation and therefore were attributed to secondary effects of cytokine or growth factor release triggered by TGF-␤.…”

Section: Discussionmentioning

confidence: 70%

Transforming Growth Factor-β (TGF-β) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic Fibrosis in Coordination with the SMAD Pathway

Tang

Heller

Meng

et al. 2017

Journal of Biological Chemistry

227

195

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Edited by Xiao-Fan WangTransforming growth factor-␤ (TGF-␤) signals through both SMAD and non-SMAD pathways to elicit a wide array of biological effects. Existing data have shown the association and coordination between STATs and SMADs in mediating TGF-␤ functions in hepatic cells, but it is not clear how STATs are activated under these circumstances. Here, we report that JAK1 is a constitutive TGF␤RI binding protein and is absolutely required for phosphorylation of STATs in a SMAD-independent manner within minutes of TGF-␤ stimulation. Following the activation of SMADs, TGF-␤ also induces a second phase of STAT phosphorylation that requires SMADs, de novo protein synthesis, and contribution from JAK1. Our global gene expression profiling indicates that the non-SMAD JAK1/STAT pathway is essential for the expression of a subset of TGF-␤ target genes in hepatic stellate cells, and the cooperation between the JAK1-STAT3 and SMAD pathways is critical to the roles of TGF-␤ in liver fibrosis.

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Stat3 signaling activation crosslinking of TGF-β1 in hepatic stellate cell exacerbates liver injury and fibrosis

Abstract: We provide a novel role of Stat3 cooperating TGF-β1 in activation and anti-apoptotic effect of HSCs. Stat3 worsens liver fibrosis through the up-regulation of TGF-β1 and fibrotic product expression.

Cited by 72 publications

References 21 publications

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Transforming Growth Factor-β (TGF-β) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic Fibrosis in Coordination with the SMAD Pathway

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