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.
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$37.50
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.