Endoplasmic reticulum-mediated induction of interleukin-8 occurs by hepatitis B virus infection and contributes to suppression of interferon responsiveness in human hepatocytes

Masataka Tsuge; Nobuhiko Hiraga; Yizhou Zhang; Misa Yamashita; Ojiro Sato; Naoya Oka; Kanma Shiraishi; Yu Izaki; Grace Naswa Makokha; Takuro Uchida; Mio Kurihara; Motonobu Nomura; Ken Tsushima; Takashi Nakahara; Eisuke Murakami; Hiromi Abe-Chayama; Tomokazu Kawaoka; Daiki Miki; Michio Imamura; Yoshiiku Kawakami; Hiroshi Aikata; Hidenori Ochi; C Nelson Hayes; Takashi Fujita; Kazuaki Chayama

doi:10.1016/j.virol.2018.08.020

Endoplasmic reticulum-mediated induction of interleukin-8 occurs by hepatitis B virus infection and contributes to suppression of interferon responsiveness in human hepatocytes

Virology. 2018 Dec:525:48-61. doi: 10.1016/j.virol.2018.08.020. Epub 2018 Sep 18.

Authors

Masataka Tsuge¹, Nobuhiko Hiraga², Yizhou Zhang³, Misa Yamashita⁴, Ojiro Sato⁵, Naoya Oka⁶, Kanma Shiraishi⁷, Yu Izaki⁸, Grace Naswa Makokha⁹, Takuro Uchida¹⁰, Mio Kurihara¹¹, Motonobu Nomura¹², Ken Tsushima¹³, Takashi Nakahara¹⁴, Eisuke Murakami¹⁵, Hiromi Abe-Chayama¹⁶, Tomokazu Kawaoka¹⁷, Daiki Miki¹⁸, Michio Imamura¹⁹, Yoshiiku Kawakami²⁰, Hiroshi Aikata²¹, Hidenori Ochi²², C Nelson Hayes²³, Takashi Fujita²⁴, Kazuaki Chayama²⁵

Affiliations

¹ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: tsuge@hiroshima-u.ac.jp.
² Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: hiraga04@hiroshima-u.ac.jp.
³ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: zhangyizhou10@yahoo.co.jp.
⁴ Hiroshima Prefectural Hospital, Hiroshima, Japan. Electronic address: m.century.lv.0131@gmail.com.
⁵ Hiroshima University, Hiroshima, Japan. Electronic address: b122558@hiroshima-u.ac.jp.
⁶ Hiroshima University, Hiroshima, Japan. Electronic address: b136015@hiroshima-u.ac.jp.
⁷ Hiroshima University, Hiroshima, Japan. Electronic address: b133350@hiroshima-u.ac.jp.
⁸ Department of Surgery, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan. Electronic address: blaugrana.jp@gmail.com.
⁹ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: gnaswa@hiroshima-u.ac.jp.
¹⁰ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: tuchida@hiroshima-u.ac.jp.
¹¹ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: sskmio@hiroshima-u.ac.jp.
¹² Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: nomuramo@hiroshima-u.ac.jp.
¹³ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: kenken0121@hiroshima-u.ac.jp.
¹⁴ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: nakahara@hiroshima-u.ac.jp.
¹⁵ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: emusuke@hiroshima-u.ac.jp.
¹⁶ Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address: habe@hiroshima-u.ac.jp.
¹⁷ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: kawaokatomo@hiroshima-u.ac.jp.
¹⁸ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan. Electronic address: daikimiki@hiroshima-u.ac.jp.
¹⁹ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: mimamura@hiroshima-u.ac.jp.
²⁰ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: kamy4419@hiroshima-u.ac.jp.
²¹ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: aikata@hiroshima-u.ac.jp.
²² Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: hochi@hiroshima-u.ac.jp.
²³ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan. Electronic address: nelsonhayes@hiroshima-u.ac.jp.
²⁴ Laboratory of Molecular Genetics, Department of Genetics and Molecular Biology, Institute for Virus Research Kyoto University, Kyoto, Japan. Electronic address: tfujita@virus.kyoto-u.ac.jp.
²⁵ Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan. Electronic address: chayama@hiroshima-u.ac.jp.

PMID: 30240958
DOI: 10.1016/j.virol.2018.08.020

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.

Keywords: Endoplasmic reticulum stress; HBV; IL-8; Immune response; Interferon responsiveness.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Endoplasmic Reticulum / metabolism*
Hepatitis B virus / physiology*
Hepatitis B, Chronic / immunology
Hepatitis B, Chronic / metabolism*
Hepatocytes / metabolism
Hepatocytes / virology*
Humans
Interleukin-8 / metabolism*
Liver / metabolism
Mice
Stress, Physiological
Up-Regulation

Substances

Interleukin-8