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

Gene Therapy volume 15, pages 277–288 (2008)Cite this article

Abstract

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.

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Acknowledgements

We thank Gloria Gonzalez-Aseguinolaza (Division Hepatology and Gene Therapy, University of Navarra, Spain) for the IFN-γ R−/− knockout mice. We appreciate scientific feedback obtained from Ricky Johnstone (Peter MacCallum Cancer Centre, Australia) and Howard Young (National Cancer Institute, USA). This project was founded through the UTE project CIMA, DIGNA Biotech and Grants from Education Department, Gobierno de Navarra and Fondo de Investigacion Sanitaria (FIS) and CIBERehd. RHA is a recipient of Ramon y Cajal research contract. MGK is a recipient of an FIS research contract. IM is a recipient of a Torres Quevedo contract.

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Author notes

  1. M G Kramer

    Present address: 6Current address: Peter MacCallum Cancer Research Institute, Cancer Immunology Program, St Andrews Place, East Melbourne 3001, Australia.,

  2. R Hernandez-Alcoceba and M G Kramer: RHA and MGK share senior authorship.

Authors and Affiliations

  1. Division of Hepatology and Gene Therapy, School of Medicine, Foundation for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain

    M Reboredo, M Zabala, I Mauleon, J Prieto, R Hernandez-Alcoceba & M G Kramer

  2. Bioinformatics and Functional Genomics Research Group Cancer Research Center (CIC-IBMCC, CSIC-USAL), Salamanca, Spain

    J De Las Rivas

  3. Division of Gene Therapy, University of Ulm, Ulm, Germany

    F Kreppel & S Kochanek

  4. CIBERehd, University Clinic, Navarra, Spain

    M Reboredo & J Prieto

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Correspondence to R Hernandez-Alcoceba or M G Kramer.

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Reboredo, M., Zabala, M., Mauleon, I. et al. Interleukin-12 inhibits liver-specific drug-inducible systems in vivo. Gene Ther 15, 277–288 (2008). https://doi.org/10.1038/sj.gt.3303073

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