Gene transfer of high-mobility group box 1 box-A domain in a rat acute liver failure model.

Masayuki Tanaka, Masahiro Shinoda, Atsushi Takayanagi, Go Oshima, Ryo Nishiyama, Kazumasa Fukuda, Hiroshi Yagi, Tetsu Hayashida, Yohei Masugi, Koichi Suda, Shingo Yamada, Taku Miyasho, Taizo Hibi, Yuta Abe, Minoru Kitago, Hideaki Obara, Osamu Itano, Hiroya Takeuchi, Michiie Sakamoto, Minoru Tanabe, Ikuro Maruyama, Yuko Kitagawa

文献索引：J. Surg. Res. 194(2) , 571-80, (2015)

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摘要

High-mobility group box 1 (HMGB1) has recently been identified as an important mediator of various kinds of acute and chronic inflammation. The protein encoded by the box-A domain of the HMGB1 gene is known to act as a competitive inhibitor of HMGB1. In this study, we investigated whether box-A gene transfer results in box-A protein production in rats and assessed therapeutic efficacy in vivo using an acute liver failure (ALF) model.Three types of adenovirus vectors were constructed-a wild type and two mutants-and a mutant vector was then selected based on the secretion from HeLa cells. The secreted protein was subjected to a tumor necrosis factor (TNF) production inhibition test in vitro. The vector was injected via the portal vein in healthy Wistar rats to confirm box-A protein production in the liver. The vector was then injected via the portal vein in rats with ALF.Western blot analysis showed enhanced expression of box-A protein in HeLa cells transfected with one of the mutant vectors. The culture supernatant from HeLa cells transfected with the vector inhibited TNF-α production from macrophages. Expression of box-A protein was confirmed in the transfected liver at 72 h after transfection. Transfected rats showed decreased hepatic enzymes, plasma HMGB1, and hepatic TNF-α messenger RNA levels, and histologic findings and survival were significantly improved.HMGB1 box-A gene transfer results in box-A protein production in the liver and appears to have a beneficial effect on ALF in rats.Copyright © 2015 Elsevier Inc. All rights reserved.