Interleukin-12 inhibits liver-specific drug-inducible systems in vivo
Reboredo M, Zabala M, Mauleon I, De Las Rivas J, Kreppel F, Kochanek S, Prieto J, Hernandez-Alcoceba R, Kramer MG.
Division of Hepatology and Gene Therapy, School of Medicine, Foundation for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain
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.
CITATION Gene Ther. 2008 Feb;15(4):277-88