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

AuthorsReboredo, Mercedes; De Las Rivas, Javier
Issue Date2008
PublisherNature Publishing Group
CitationGene Therapy 15: 277-288 (2008)
AbstractDrug-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.
DescriptionEl pdf del artículo es la versión de autor.-- et al.
Publisher version (URL)http://dx.doi.org/10.1038/sj.gt.3303073
Identifiersdoi: 10.1038/sj.gt.3303073
issn: 0969-7128
e-issn: 1476-5462
Appears in Collections:(IBMCC) Artículos
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