Hepatitis B Virus Core Antigen Stimulates IL-6 Expression via p38, ERK and NF-κB Pathways in Hepatocytes

Chen, Zhi; Li, Yang-Xia; Fu, Haijing; Ren, Yan; Zou, Ling; Shen, Shizhen; Chen, Ping; Sun, Ting; Huang, ChunHong

doi:10.1159/000455954

Cited by 26 publications

(29 citation statements)

References 54 publications

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“…Moreover, in the liver the imbalance of oxidant/antioxidant system can also lead to the activation of stress-sensitive signaling pathways called MAPK [34, 35]. It is also worth of note that in human hepatocarcinoma cell lines cells multiple membrane-starting pathways have been reported to be rapidly activated by the ER-estradiol complex and the blockade of phospholipase C/protein kinase C, ERK, and AKT pathways completely prevented the estradiol-induced DNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Oxidative Stress by 17 β-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro

Surico¹,

Ercoli²,

Farruggio

et al. 2017

Cell Physiol Biochem

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Background/Aims: estrogens and phytoestrogens exert hepatoprotection through mechanisms not clearly examined yet. Here, we investigated the protective effects exerted by 17β-estradiol and genistein against oxidative stress in hepatocytes and hepatic stellate cells (HSCs) and the involvement of specific receptors and the intracellular signalling. Methods: Huh7.5 and LX-2, alone or in co-culture with Huh7.5, were treated with 17β-estradiol and genistein alone or in the presence of menadione and of estrogen receptors (ERs) and G protein-coupled-estrogenic-receptors (GPER) blockers. Cell viability, mitochondrial membrane potential and oxidant/antioxidant system were measured by specific kits. Western Blot was used for the analysis of Akt and p38-mitogen-activated-protein kinases (MAPK) activation and α-smooth-muscle actin expression. Results: In Huh7.5, 17β-estradiol and genistein prevented the effects of peroxidation by modulating Akt and p38MAPK activation. Similar antioxidant and protective findings were obtained in LX-2 of co-culture experiments, only. ERs and GPER blockers were able to prevent the effects of 17β-estradiol and genistein. Conclusion: In Huh7.5 and LX-2, 17β-estradiol and genistein counteract the effects of peroxidation through the involvement of ERs and GPER and by an intracellular signalling related to Akt and p38MAPK. As concerning LX-2, paracrine factors released by Huh7.5 play a key role in protection against oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Modulation of Oxidative Stress by 17 β-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro

Surico¹,

Ercoli²,

Farruggio

et al. 2017

Cell Physiol Biochem

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“…HBx and HBc upregulated whereas HBe inhibited the expression of IL‐6 in hepatocytes . In this study, we found that HBV and its encoded protein could induce IL‐6 expression in LO2 and HepG2 cells.…”

Section: Discussionmentioning

confidence: 51%

“…Clinical research has suggested that IL‐6 serum levels are increased in HBV‐infected patients and are significantly higher in patients with severe, acute infections than patients with a chronic active infection . Other reports have stated that both HBx and HBc could upregulated IL‐6 expressions in hepatocytes …”

Section: Discussionmentioning

confidence: 99%

Induction of interleukin 6 impairs the anti‐HBV efficiency of IFN‐α in human hepatocytes through upregulation of SOCS3

Yang

Guan

Zhang

et al. 2019

Journal of Medical Virology

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Interleukin 6 (IL‐6) is a pleiotropic cytokine with pivotal functions in the regulation of the biological responses of several target cells, including hepatocytes. Previous studies have shown that serum IL‐6 levels are increased in hepatitis B patients. However, the role of IL‐6 in modulating the anti‐hepatitis B virus (HBV) activity of interferon‐α (IFN‐α) remains unclear. In this study, we found that both HBV and viral proteins could induce the expression of IL‐6 in hepatocytes (LO2 and HepG2). Exogenous IL‐6 had no effect on HBV replication, whereas knockdown of IL‐6 expression by RNAi inhibited that. Interestingly, IFN‐α markedly induced IL‐6 expression in hepatocytes, especially in HBV replicating hepatocytes. In turn, IL‐6 impaired the anti‐HBV efficiency of IFN‐α by decreases the expression of IFN‐α downstream effectors by upregulation of suppressor of cytokine signaling‐3 (SOCS3). Furthermore, we demonstrated that downregulation of SOCS3 improved IFN antiviral activity to some extent in HBV replicating hepatocytes. These data provided new insights for a better understanding of the mechanism of IFN‐α resistance and may represent a novel therapeutic strategy to efficiently target HBV infection.

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“…A previous study indicated that HBx-induced oval cell proliferation is dependent on activation of the MEK/ERK and PI3K/Akt signaling pathways [42]. Moreover, a recent study demonstrated that HBcAg activates p38, ERK, and NF-κB to enhance the production of IL-6 in hepatocytes [43]. To further evaluate the downstream effectors of IGF-IR, HCC cells were pretreated with the IGF-IR inhibitor PPP and subsequently stimulated with serum from HDs and CHB patients.…”

Section: Discussionmentioning

confidence: 99%

Serum from Chronic Hepatitis B Patients Promotes Growth and Proliferation via the IGF-II/IGF-IR/MEK/ERK Signaling Pathway in Hepatocellular Carcinoma Cells

Ji¹,

Wang²,

Chen³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Chronic hepatitis B virus (HBV) infection (CHB) plays a central role in the etiology of hepatocellular carcinoma (HCC). Emerging evidence implicates insulin-like growth factor (IGF)-II as a major risk factor for the growth and development of HCC. However, the relationship between HBV infection and IGF-II functions remains to be elucidated. Methods: Levels of circulating IGF-II and IGF-I receptor (IGF-IR) in healthy donors (HDs) and CHB patients were tested by ELISA. Human HCC cell lines (HepG-2, SMMC-7721, MHCC97-H) were incubated with serum from HDs and CHB patients at various concentrations for 24, 48, and 72 h. MTT and plate colony formation assays, BrdU ELISA, ELISA, small-interfering RNA (siRNA) transfection, quantitative real-time PCR, and western blot were applied to assess the functional and molecular mechanisms in HCC cell lines. Results: Serum levels of IGF-II and IGF-IR were significantly higher in CHB patients than in HDs. Additionally, serum from CHB patients directly induced cell growth, proliferation, IGF-II secretion, and HDGF-related protein-2 (HRP-2) and nuclear protein 1 (NUPR1) mRNA and protein expression in HCC cells. Moreover, serum from CHB patients increased IGF-II–induced cell growth, proliferation, and HRP-2 and NUPR1 mRNA and protein expression in HCC cells. Blockade of IGF-IR clearly inhibited the above effects. Most importantly, interference with IGF-II function markedly repressed the cell proliferation and HRP-2 and NUPR1 mRNA and protein expression induced by serum from CHB patients. Furthermore, serum from CHB patients induced ERK phosphorylation via IGF-IR, with the MEK inhibitor PD98059 significantly decreasing CHB patient serum-induced IGF-II secretion, cell proliferation, and HRP-2 and NUPR1 mRNA and protein expression. Conclusion: Serum from CHB patients increases cell growth and proliferation and enhances HRP-2 and NUPR1 expression in HCC cells via the IGF-II/IGF-IR/MEK/ERK signaling pathway. These findings help to explain the molecular mechanisms underlying HBV-related HCC and may lead to the development of effective therapies.

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Hepatitis B Virus Core Antigen Stimulates IL-6 Expression via p38, ERK and NF-κB Pathways in Hepatocytes

Cited by 26 publications

References 54 publications

Modulation of Oxidative Stress by 17 β-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro

Modulation of Oxidative Stress by 17 β-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro

Induction of interleukin 6 impairs the anti‐HBV efficiency of IFN‐α in human hepatocytes through upregulation of SOCS3

Serum from Chronic Hepatitis B Patients Promotes Growth and Proliferation via the IGF-II/IGF-IR/MEK/ERK Signaling Pathway in Hepatocellular Carcinoma Cells

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