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Early hepatotoxicity is considered to involve inflammatory cytokines; however, the precise mechanism remains to be clarified. We examined the mechanism of early Ad vector\u2013induced 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\u2032 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\u2013treated hepatocytes in the presence of IL-6 were significantly suppressed upon inhibition of JAK and STAT3. Ad vector\u2013mediated acute hepatotoxicities and leaky Ad expression were significantly reduced in IL-6 knockout mice compared with those in wild-type mice. Thus, Ad vector\u2013induced IL-6 promotes leaky Ad gene expression, leading to acute hepatotoxicity.<\/jats:p>","DOI":"10.4049\/jimmunol.2000830","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T23:05:51Z","timestamp":1607123151000},"page":"410-421","source":"Crossref","is-referenced-by-count":20,"title":["Adenovirus Vector\u2013Induced IL-6 Promotes Leaky Adenoviral Gene Expression, Leading to Acute Hepatotoxicity"],"prefix":"10.1093","volume":"206","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1574-5526","authenticated-orcid":false,"given":"Kahori","family":"Shimizu","sequence":"first","affiliation":[{"name":"Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University , Osaka 565-0871 ,","place":["Japan"]},{"name":"Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University , Osaka 584-8540 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