Interleukin-12 inhibits liver-specific drug-inducible systems in vivo

• Published in: Gene therapy Vol. 15; no. 4; pp. 277 - 288
• Main Authors: Reboredo, M, Zabala, M, Mauleon, I, De Las Rivas, J, Kreppel, F, Kochanek, S, Prieto, J, Hernandez-Alcoceba, R, Kramer, M G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2008; Nature Publishing Group
• Subjects: Adenoviridae - genetics; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; Biological activity; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; Butyrates - pharmacology; Cell Biology; Cytokines; Deacetylation; DNA microarrays; Down-Regulation; Doxycycline; Doxycycline - pharmacology; Drug therapy; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Silencing; Gene Therapy; Genetic Vectors; Genomes; Health. Pharmaceutical industry; Histone deacetylase; Histone Deacetylase Inhibitors; Human Genetics; Industrial applications and implications. Economical aspects; Interferon-gamma - biosynthesis; Interferon-gamma - physiology; Interleukin 12; Interleukin-12 - genetics; Liver; Liver - drug effects; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mifepristone; Mifepristone - pharmacology; Nanotechnology; original-article; Promoter Regions, Genetic; RNA, Messenger - genetics; Sodium butyrate; Transcription; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; γ-Interferon; interferon-γ; liver; histone deacetylase; silencing; interleukin-12; Drug; Histone deacetylase; Digestive system; Liver; Cytokine; Interleukin 12; In vivo; Inhibition; Gene therapy; Gamma interferon
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3303073

Drug-inducible systems allow modulation of the duration and intensity of cytokine expression in liver immuno-based gene therapy protocols. However, the biological activity of the transgene may influence their function. We have analyzed the kinetics of interleukin-12 (IL-12) expression controlled by the doxycycline (Dox)- and the mifepristone (Mif)-dependent systems using two long-term expressing vectors directed to liver: a plasmid administered by hydrodynamic injection and a high-capacity adenoviral vector. Daily administration of Dox or Mif was associated with a progressive loss of inducibility and a decrease of murine IL-12 production. This inhibition occurred at the transcriptional level and was probably caused by an interferon (IFN)-γ-mediated downmodulation of liver-specific promoters that control the expression of transactivators in these systems. Genome-wide expression microarrays studies revealed a parallel downregulation of liver-specific genes in mice overexpressing murine IL-12. However, a promoter naturally induced by IL-12 was also inhibited by this cytokine when placed in a plasmid vector. Interestingly, treatment with sodium butyrate, a class I/II histone deacetylase inhibitor, was able to rescue liver-specific promoter activity solely in the vector. We conclude that biologically active IL-12 can transiently inhibit the function of drug-inducible systems in non-integrative DNA vectors by reducing promoter activity, probably through IFN-γ and protein deacetylation-dependent mechanisms.