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| Título: | Interleukin-12 inhibits liver-specific drug-inducible systems in vivo |
Autor: | Reboredo, Mercedes; De Las Rivas, Javier CSIC ORCID CVN | Fecha de publicación: | 2008 | Editor: | Nature Publishing Group | Citación: | Gene Therapy 15: 277-288 (2008) | Resumen: | 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. | Descripción: | El pdf del artículo es la versión de autor.-- et al. | Versión del editor: | http://dx.doi.org/10.1038/sj.gt.3303073 | URI: | http://hdl.handle.net/10261/60694 | DOI: | 10.1038/sj.gt.3303073 | Identificadores: | doi: 10.1038/sj.gt.3303073 issn: 0969-7128 e-issn: 1476-5462 |
| Aparece en las colecciones: | (IBMCC) Artículos |
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| INTERLEUKIN-12.pdf | 3,33 MB | Adobe PDF |  Visualizar/Abrir |
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