Inflammatory cell-specific transgene expression system responding to Iκ-B kinase beta activation

Daisuke Asai, Akira Tsuchiya, Jeong Hun Kang, Kenji Kawamura, Jun Oishi, Takeshi Mori, Takuro Niidome, Yoko Shoji, Hideki Nakashima, Yoshiki Katayama

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19 Citations (Scopus)

Abstract

Background: Control of inflammation is essential for the clinical management of many common human diseases. However, there are few generally applicable strategies to convert an abnormal intracellular signal into a gene expression that leads to normalization of the intracellular environment. Recently, we proposed a novel strategy termed D-RECS (i.e. drug or gene delivery system responding to cellular signals) to convert an intracellular signal to transgene expression. In the present study, we applied this concept to inflammatory cells using Iκ-B kinase as a signal molecule that triggers the gene expression. Methods: Candidate cationic substrates of Iκ-B kinase (IKK)β were synthesized and their reactivity was investigated. Then, polymers grafted with these peptides were prepared by radical polymerization. Polymer/DNA complexes (polyplexes) were prepared by mixing plasmid DNAs with the polymers. The behaviour of these polyplexes by adding IKKβ was examined. Furthermore, changes of gene expression were evaluated after the microinjection of polyplex into living cells under conditions of nuclear factor (NF)-κB activation. Results: Synthetic peptides with additional lysine residues were well phosphorylated by IKKβ. Both the polymer and the polyplex were also phosphorylated by IKKβ. The results of gel shift assay showed that the polyplex was disintegrated and free DNA was released in the presence of IKKβ. The polyplex comprising-green fluorescent protein plasmid DNA and the polymer expressed the transgene in living cells exposed to a pro-inflammatory stimulus. Conclusions: Our concept of cell-specific gene expression was demonstrated to work in inflammatory cells. This method may provide a unique strategy for gene therapy exclusively in inflammatory cells.

Original languageEnglish
Pages (from-to)624-632
Number of pages9
JournalJournal of Gene Medicine
Volume11
Issue number7
DOIs
Publication statusPublished - Oct 2 2009

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Drug Discovery
  • Genetics(clinical)

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