Transcriptional re-programming of primary macrophages reveals distinct apoptotic and anti-tumoral functions of IRF-3 and IRF-7.
The immunoregulatory transcriptional modulators - IFN-regulatory factor (IRF)-3 and IRF-7 - possess similar structural features but distinct gene-regulatory potentials. For example, adenovirus-mediated transduction of the constitutively active form of IRF-3 triggered cell death in primary human MPhi, whereas expression of active IRF-7 induced a strong anti-tumoral activity in vitro. To further characterize target genes involved in these distinct cellular responses, transcriptional profiles of active IRF-3- or IRF-7-transduced primary human MPhi were compared and used to direct further mechanistic studies. The pro-apoptotic BH3-only protein Noxa was identified as a primary IRF-3 target gene and an essential regulator of IRF-3, dsRNA and vesicular stomatitis virus-induced cell death. The critical role of IRF-7 and type I IFN production in increasing the immunostimulatory capacity of MPhi was also evaluated; IRF-7 increased the expression of a broad range of IFN-stimulated genes including immunomodulatory cytokines and genes involved in antigen processing and presentation. Furthermore, active IRF-7 augmented the cross-presentation capacity and tumoricidal activity of MPhi and led to an anti-tumor response against the B16 melanoma model in vivo. Altogether, these data further highlight the respective functions of IRF-3 and IRF-7 to program apoptotic, immune and anti-tumor responses.
Goubau
Delphine
D
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, Montreal, Que, Canada.
Romieu-Mourez
Raphaëlle
R
Solis
Mayra
M
Hernandez
Eduardo
E
Mesplède
Thibault
T
Lin
Rongtuan
R
Leaman
Douglas
D
Hiscott
John
J
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000502:physiology*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009369:Neoplasms / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D014158:Transcription, Genetic; D014161:Transduction, Genetic
D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2