Virology. 2018 Sep 18;525:48-61. doi: 10.1016/j.virol.2018.08.020. [Epub ahead of print]
Endoplasmic reticulum-mediated induction of interleukin-8 occurs by hepatitis B virus infection and contributes to suppression of interferon responsiveness in human hepatocytes.
Tsuge M1, Hiraga N2, Zhang Y3, Yamashita M4, Sato O5, Oka N6, Shiraishi K7, Izaki Y8, Makokha GN9, Uchida T10, Kurihara M11, Nomura M12, Tsushima K13, Nakahara T14, Murakami E15, Abe-Chayama H16, Kawaoka T17, Miki D18, Imamura M19, Kawakami Y20, Aikata H21, Ochi H22, Hayes CN23, Fujita T24, Chayama K25.
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Abstract
The events in the immune response to hepatitis B virus (HBV) remain unclear. We analyzed the direct influence of HBV on gene expression in human hepatocytes under immunodeficient conditions using a human hepatocyte chimeric mouse model. HBV-infected or non-infected chimeric mouse livers were collected, and gene expression profiles were compared. Since IL-8 was the most significantly up-regulated gene at 8 weeks after HBV infection, we focused on IL-8 and found that HBx and the large HBs (L-HBs) protein induce transcription of IL-8 via endoplasmic reticulum stress. This stress induces IL-8 transcription via NFAT activation and contributes to suppression of interferon responsiveness in HBV-infected human hepatocytes. In the present study, we identified a novel regulatory mechanism in which the L-HBs protein activates IL-8 via endoplasmic reticulum stress, suggesting a key role for IL-8 in the immune response to HBV and a potential new target for antiviral treatments of HBV infection.
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