This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Romieu-Mourez, R. Articles by Hiscott, J. Search for Related Content PubMed PubMed Citation Articles by Romieu-Mourez, R. Articles by Hiscott, J.

Distinct Roles for IFN Regulatory Factor (IRF)-3 and IRF-7 in the Activation of Antitumor Properties of Human Macrophages

¹ Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research and Departments of Microbiology and Immunology and Medicine, McGill University; ² Biotechnology Research Institute, Montreal, Quebec, Canada; and ³ Immuno-Designed Molecules, Paris, France

Requests for reprints: John Hiscott, Lady Davis Institute, McGill University, 3755 Cote Ste. Catherine, Montreal, Quebec, Canada H3T 1E2. Phone: 514-340-8222; Fax: 514-340-7576; E-mail: john.hiscott{at}mcgill.ca.

When properly activated, macrophages can be tumoricidal, thus making them attractive additions to standard cancer therapies. To this end, tolerance and activity of human autologous IFN--activated macrophages, produced in large scale for clinical use (MAK cells), have been assessed in pilot trials in cancer patients. In the present study, we tested the hypothesis that activation of IFN regulatory factor (IRF)-3 and IRF-7, with subsequent type I IFN production, may be involved in the acquisition of new antitumor functions by macrophages. Adenoviral vectors were generated for the delivery of constitutively active forms of IRF-3 (Ad-IRF-3) or IRF-7 (Ad-IRF-7) into primary human macrophages. Cell death was observed in Ad-IRF-3-transduced macrophages, whereas Ad-IRF-7-transduced macrophages produced type I IFNs and displayed increased expression of genes encoding tumor necrosis factor (TNF)–related apoptosis-inducing ligand, interleukin (IL)-12, IL-15, and CD80, persisting for at least 96 hours. Expression of iNOS, TNF-, FasL, IL-1, and IL-6 genes was unaltered by Ad-IRF-7 transduction. Interestingly, Ad-IRF-3 or Ad-IRF-7 transduction negatively regulated the transcription of protumorigenic genes encoding vascular endothelial growth factor and matrix metalloproteinase-2. Furthermore, Ad-IRF-7-transduced macrophages exerted a cytostatic activity on different cancer cell lines, including SK-BR-3, MCF-7, and COLO-205; the latter cells were shown previously to be insensitive to MAK cells. In conclusion, transduction of active forms of IRF-3 or IRF-7 differentially modulate the apoptotic and antitumor properties of primary macrophages, with active IRF-7 leading to the acquisition of novel antitumor effector functions. (Cancer Res 2006; 66(21): 10576-85)

This article has been cited by other articles:

				H. Kaku and T. L. Rothstein Fas Apoptosis Inhibitory Molecule Enhances CD40 Signaling in B Cells and Augments the Plasma Cell Compartment J. Immunol., August 1, 2009; 183(3): 1667 - 1674. [Abstract] [Full Text] [PDF]

				R. Romieu-Mourez, M. Francois, M.-N. Boivin, M. Bouchentouf, D. E. Spaner, and J. Galipeau Cytokine Modulation of TLR Expression and Activation in Mesenchymal Stromal Cells Leads to a Proinflammatory Phenotype J. Immunol., June 15, 2009; 182(12): 7963 - 7973. [Abstract] [Full Text] [PDF]

				L. Wu, E. Fossum, C. H. Joo, K.-S. Inn, Y. C. Shin, E. Johannsen, L. M. Hutt-Fletcher, J. Hass, and J. U. Jung Epstein-Barr Virus LF2: an Antagonist to Type I Interferon J. Virol., January 15, 2009; 83(2): 1140 - 1146. [Abstract] [Full Text] [PDF]

				T. Reimer, M. Brcic, M. Schweizer, and T. W. Jungi poly(I:C) and LPS induce distinct IRF3 and NF-{kappa}B signaling during type-I IFN and TNF responses in human macrophages J. Leukoc. Biol., May 1, 2008; 83(5): 1249 - 1257. [Abstract] [Full Text] [PDF]

				F. R. Okamba, E. Moreau, K. Cheikh Saad Bouh, C. A. Gagnon, B. Massie, and M. Arella Immune Responses Induced by Replication-Defective Adenovirus Expressing the C-Terminal Portion of the Mycoplasma hyopneumoniae P97 Adhesin Clin. Vaccine Immunol., June 1, 2007; 14(6): 767 - 774. [Abstract] [Full Text] [PDF]

				J. Hiscott Triggering the Innate Antiviral Response through IRF-3 Activation J. Biol. Chem., May 25, 2007; 282(21): 15325 - 15329. [Abstract] [Full Text] [PDF]