<scp>ULBP</scp>1 is induced by hepatitis C virus infection and is the target of the <scp>NK</scp> cell‐mediated innate immune response in human hepatocytes

Dansako, Hiromichi; Imai, Hideki; Ueda, Youki; Satoh, Shinya; Wakita, Takaji; Kato, Naoya

doi:10.1002/2211-5463.12373

Cited by 8 publications

(10 citation statements)

References 31 publications

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“…Cell surface expression of exogenous NTCP was detected by a flow cytometer as previously reported . Anti‐Myc (PL14; Medical & Biological Laboratories), and FITC‐conjugated goat anti‐mouse antibody (Jackson ImmunoResearch Laboratories, West Grove, PA, USA) were used as primary and secondary antibody, respectively.…”

Section: Methodsmentioning

confidence: 99%

High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

et al. 2018

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Hepatitis B virus (HBV) is a hepatotropic DNA virus causing hepatic diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. To study HBV, human hepatoma HepG2 cells are currently used as an HBV infectious cell culture model worldwide. HepG2 cells exhibit susceptibility to HBV by exogenously expressing sodium taurocholate cotransporting polypeptide (NTCP). We herein demonstrated that human immortalized hepatocyte NKNT-3 cells exhibited susceptibility to HBV by exogenously expressing NTCP (NKNT-3/NTCP cells). By comparing cyclic GMP-AMP synthetase (cGAS)-stimulator of interferon genes (STING) signaling pathway in several NKNT-3/NTCP cell-derived cell clones, we found that STING was highly expressed in cell clones exhibiting resistance but not susceptibility to HBV. High-level expression of STING was implicated in HBV-triggered induction of type III IFN and a pro-inflammatory cytokine, IL-6. In contrast, RNAi-mediated knockdown of STING inhibited type III IFN induction and restored the levels of HBV total transcript in an HBV-infected cell clone exhibiting resistance to HBV. These results suggest that STING regulates susceptibility to HBV by its expression levels. STING may thus be a novel target for anti-HBV strategies. K E Y W O R D Shepatitis B virus, hepatocellular carcinoma, host innate immune response, STING, type III interferon

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Section: Methodsmentioning

confidence: 99%

High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

et al. 2018

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“…In HCV or HBV infected patients, high levels of NKG2D expression on intrahepatic T cells ( 112 ), NK ( 79 , 113 – 115 ), and iNKT cells ( 116 ) have been reported. During the course of HCV infection, MICA/B expression is elevated compared to healthy individuals ( 79 ) and HCV proteins were shown to enhance cell surface expression of ULBP-1 on human immortalized hepatocytes ( 117 ). Expression of MICA and MICB on transformed hepatocytes was also observed on hepatoma cell lines, HCCs ( 80 , 118 ), and carcinoma cell lines ( 119 ).…”

Section: Hepatocellular Carcinoma (Hcc)-nkg2d Ligand Expression In a mentioning

confidence: 99%

The Paradoxical Role of NKG2D in Cancer Immunity

et al. 2018

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The activating receptor NKG2D and its ligands are recognized as a potent immune axis that controls tumor growth and microbial infections. With regards to cancer surveillance, various studies have demonstrated the antitumor function mediated by NKG2D on natural killer cells and on conventional and unconventional T cells. The use of NKG2D-deficient mice established the importance of NKG2D in delaying tumor development in transgenic mouse models of cancer. However, we recently demonstrated an unexpected, flip side to this coin, the ability for NKG2D to contribute to tumor growth in a model of inflammation-driven liver cancer. With a focus on the liver, here, we review current knowledge of NKG2D-mediated tumor surveillance and discuss evidence supporting a dual role for NKG2D in cancer immunity. We postulate that in certain advanced cancers, expression of ligands for NKG2D can drive cancer progression rather than rejection. We propose that the nature of the microenvironment within and surrounding tumors impacts the outcome of NKG2D activation. In a form of autoimmune attack, NKG2D promotes tissue damage, mostly in the inflamed tissue adjacent to the tumor, facilitating tumor progression while being ineffective at rejecting transformed cells in the tumor bed.

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“…TB Green Premix Ex Taq Kit (Takara Bio) and a realtime LightCycler PCR system (Roche Diagnostics, Basel, Switzerland) were used to perform quantitative RT-PCR analysis. The primer sets for IFN-b [18], IFN-l1 [17], IFN-l2/3 [17], IFN-g [19], ISG56 [20], cGAS [15], and GAPDH [20] were used for quantitative RT-PCR analysis as previously described. We also prepared the following forward and reverse primer sets for ISG15: 5 0 -GCC TTCCAGCAGCGTCTGGC-3' (forward) and 5 0 -GCAGGCGCAGATTCAT GAACACGG-3' (reverse).…”

Section: Quantitative Rt-pcr Analysismentioning

confidence: 99%

Daunorubicin, a topoisomerase II poison, suppresses viral production of hepatitis B virus by inducing cGAS-dependent innate immune response

Imai

Dansako

Ueda

et al. 2018

Biochemical and Biophysical Research Communications

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Hepatitis B virus (HBV) causes hepatic diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. These diseases are closely associated with persistent HBV infection. To prevent the progression of hepatic diseases, it is thus important to suppress persistent HBV infection. Daunorubicin (DNR), a topoisomerase II (Top II) poison, is a clinically used anticancer agent with a wide spectrum of activity against malignancies. DNR was recently reported to cause DNA damage-dependent interferon (IFN)-β induction through exogenous cyclic GMP-AMP synthetase (cGAS) and subsequently to suppress Ebola virus replication. In the present study, we demonstrated that DNR caused the inhibition of cell proliferation, but not cell death, through the DNA damage response in immortalized human hepatocyte NKNT-3/NTCP cells. Interestingly, DNR triggered the endogenous cGAS-dependent innate immune response and subsequently suppressed viral production of HBV in NKNT-3/NTCP cells. Top II poisons may be anti-HBV drug candidates.

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ULBP1 is induced by hepatitis C virus infection and is the target of the NK cell‐mediated innate immune response in human hepatocytes

Cited by 8 publications

References 31 publications

High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

The Paradoxical Role of NKG2D in Cancer Immunity

Daunorubicin, a topoisomerase II poison, suppresses viral production of hepatitis B virus by inducing cGAS-dependent innate immune response

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