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Adenovirus Vector–Induced IL-6 Promotes Leaky Adenoviral Gene Expression, Leading to Acute Hepatotoxicity

Kahori Shimizu, Fuminori Sakurai, Shunsuke Iizuka, Ryosuke Ono, Tomohito Tsukamoto, Fumitaka Nishimae, Shin-ichiro Nakamura, Toru Nishinaka, Tomoyuki Terada, Yasushi Fujio and Hiroyuki Mizuguchi
J Immunol January 15, 2021, 206 (2) 410-421; DOI: https://doi.org/10.4049/jimmunol.2000830
Kahori Shimizu
*Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;
†Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka 584-8540, Japan;
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  • ORCID record for Kahori Shimizu
Fuminori Sakurai
*Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;
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Shunsuke Iizuka
*Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;
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Ryosuke Ono
*Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;
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Tomohito Tsukamoto
*Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;
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Fumitaka Nishimae
*Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;
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Shin-ichiro Nakamura
‡Research Center of Animal Life Science, Shiga University of Medical Science, Shiga 520-2192, Japan;
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Toru Nishinaka
†Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka 584-8540, Japan;
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Tomoyuki Terada
†Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka 584-8540, Japan;
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Yasushi Fujio
§Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;
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Hiroyuki Mizuguchi
*Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;
¶The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka 565-0871, Japan;
‖Laboratory of Hepatocyte Differentiation, National Institute of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; and
#Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka 565-0871, Japan
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Key Points

  • Suppression of leaky Ad gene expression in the liver attenuated acute hepatotoxicity.

  • IL-6 enhanced leaky Ad gene expression and Ad vector–induced cytotoxicity.

  • Acute hepatotoxicity and leaky Ad gene expression were reduced in IL-6 KO mice.

Abstract

Adenovirus (Ad) vector–mediated transduction can cause hepatotoxicity during two phases, at ∼2 and 10 days after administration. Early hepatotoxicity is considered to involve inflammatory cytokines; however, the precise mechanism remains to be clarified. We examined the mechanism of early Ad vector–induced hepatotoxicity by using a conventional Ad vector, Ad-CAL2, and a modified Ad vector, Ad-E4-122aT-CAL2. Ad-E4-122aT-CAL2 harbors sequences complementary to the liver-specific miR-122a in the 3′ untranslated region of E4, leading to significant suppression of leaky Ad gene expression in the liver via posttranscriptional gene silencing and a significant reduction in late-phase hepatotoxicity. We found that Ad-E4-122aT-CAL2 transduction significantly attenuated acute hepatotoxicity, although Ad-E4-122aT-CAL2 and Ad-CAL2 induced comparable cytokine expression levels in the liver and spleen. IL-6, a major inflammatory cytokine induced by Ad vectors, significantly enhanced leaky Ad gene expression and cytotoxicity in primary mouse hepatocytes following Ad-CAL2 but not Ad-E4-122aT-CAL2 transduction. Furthermore, leaky Ad gene expression and cytotoxicity in Ad-CAL2–treated hepatocytes in the presence of IL-6 were significantly suppressed upon inhibition of JAK and STAT3. Ad vector–mediated acute hepatotoxicities and leaky Ad expression were significantly reduced in IL-6 knockout mice compared with those in wild-type mice. Thus, Ad vector–induced IL-6 promotes leaky Ad gene expression, leading to acute hepatotoxicity.

This article is featured in Top Reads, p.243

Footnotes

  • This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI (grants 23689010, 17H00863, JP15K18939, and JP18K14964), the Japan Agency for Medical Research and Development (Grant 17am0101084j0001), grants from the Ministry of Health, Labor and Welfare of Japan, Osaka Ohtani University, the Sumitomo Electric Industries Group Corporate Social Responsibility Foundation, and Takara Bio. K.S. and S.I. were Research Fellows of the JSPS.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    Ad
    adenovirus
    ALT
    alanine aminotransferase
    DKO
    double-knockout
    KO
    knockout
    LDH
    lactate dehydrogenase
    RT-qPCR
    quantitative RT-PCR
    VP
    virus particle.

  • Received July 23, 2020.
  • Accepted November 4, 2020.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (2)
The Journal of Immunology
Vol. 206, Issue 2
15 Jan 2021
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Adenovirus Vector–Induced IL-6 Promotes Leaky Adenoviral Gene Expression, Leading to Acute Hepatotoxicity
Kahori Shimizu, Fuminori Sakurai, Shunsuke Iizuka, Ryosuke Ono, Tomohito Tsukamoto, Fumitaka Nishimae, Shin-ichiro Nakamura, Toru Nishinaka, Tomoyuki Terada, Yasushi Fujio, Hiroyuki Mizuguchi
The Journal of Immunology January 15, 2021, 206 (2) 410-421; DOI: 10.4049/jimmunol.2000830

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Adenovirus Vector–Induced IL-6 Promotes Leaky Adenoviral Gene Expression, Leading to Acute Hepatotoxicity
Kahori Shimizu, Fuminori Sakurai, Shunsuke Iizuka, Ryosuke Ono, Tomohito Tsukamoto, Fumitaka Nishimae, Shin-ichiro Nakamura, Toru Nishinaka, Tomoyuki Terada, Yasushi Fujio, Hiroyuki Mizuguchi
The Journal of Immunology January 15, 2021, 206 (2) 410-421; DOI: 10.4049/jimmunol.2000830
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Print ISSN 0022-1767        Online ISSN 1550-6606