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

Gene Ther. 2008 Feb;15(4):277-88. doi: 10.1038/ Epub 2007 Nov 22.


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)-gamma-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-gamma and protein deacetylation-dependent mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Butyrates / pharmacology
  • Down-Regulation
  • Doxycycline / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Gene Expression
  • Gene Silencing
  • Genetic Vectors
  • Histone Deacetylase Inhibitors
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / physiology
  • Interleukin-12 / genetics*
  • Liver / drug effects*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mifepristone / pharmacology
  • Promoter Regions, Genetic
  • RNA, Messenger / genetics


  • Butyrates
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • RNA, Messenger
  • Interleukin-12
  • Mifepristone
  • Interferon-gamma
  • Doxycycline