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
Revista: Gene Therapy
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.
CITA DEL ARTÍCULO Gene Ther. 2008 Feb;15(4):277-88
tal vezLE INTERESE
La Clínica es el hospital privado con mayor dotación tecnológica de España, todo en un único centro.
Los profesionales de la Clínica realizan una labor continuada de investigación y formación, siempre en beneficio del paciente.
Conozca por qué somos diferentes a otros centros sanitarios. Calidad, rapidez, comodidad y resultados.