Positive correlation between the generation of reactive oxygen species and activation/reactivation of transgene expression after hydrodynamic injections into mice

Naomi Takiguchi, Yuki Takahashi, Makiya Nishikawa, Yuriko Matsui, Yasushi Fukuhara, Daihi Oushiki, Kazuki Kiyose, Kenjiro Hanaoka, Tetsuo Nagano, Yoshinobu Takakura

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Purpose: Hydrodynamic injection has been shown to reactivate silenced transgene expression in mouse liver. In this study, the roles of inflammatory cytokines and reactive oxygen species (ROS) in the reactivation were examined. Methods: Production of inflammatory cytokines and ROS by hydrodynamic injection of saline was examined in mice that had received a hydrodynamic injection of a plasmid expressing Gaussia luciferase. The level of reporter gene expression was used as an indicator of the reactivation. The involvement of cytokines and ROS was examined by depleting Kupffer cells or by pre-administration of antioxidants, respectively. Results: A hydrodynamic injection of saline induced a significant production of interleukin (IL)-6. Depleting Kupffer cells using clodronate liposomes markedly reduced the IL-6 production but had no significant effect on the transgene expression. On the other hand, an injection of catalase or N-acetylcysteine significantly inhibited the hydrodynamic injection-induced reactivation of silenced transgene expression. The silenced expression was also reactivated by carbon tetrachloride, an inducer of oxidative stress in the liver, in a dose-dependent manner, and this reactivation was significantly inhibited by catalase. Conclusions: These findings show a positive correlation between the generation of ROS and the reactivation of silenced transgene expression after hydrodynamic injections.

Original languageEnglish
Pages (from-to)702-711
Number of pages10
JournalPharmaceutical research
Volume28
Issue number4
DOIs
Publication statusPublished - 2011 Apr
Externally publishedYes

Keywords

  • hydrodynamic injection
  • inflammation
  • liver
  • plasmid DNA
  • reactive oxygen species

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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