Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and control of anti-tumor activity in primary macrophages.
Type I IFN (IFN-alpha/beta) have important biological functions ranging from immune cell development and activation, to tumor cell killing and most importantly inhibition of virus replication. Following viral infection or activation of Toll-like receptors (TLRs) via distinct ligands, IFN-alpha/beta are produced. Two members of the interferon regulatory factor (IRF) family - IRF-3 and IRF-7 - are the major modulators of IFN gene expression. Activation of IRF-3 and IRF-7 by TBK1/IKKvarepsilon mediated phosphorylation promotes IFN gene expression and potentiates the production of IFN responsive genes important to the development of an effective antiviral immune response. IFN treatment can augment anti-tumor properties and they are potentially key players in cancer therapy. For example, adoptive transfer of IFN-gamma-activated macrophages can mediate tumor cell killing via direct cell-cell contact, as well as release of soluble cytotoxic pro-inflammatory molecules. A recent study investigated whether IRF-3 and IRF-7 could mediate the acquisition of new anti-tumor effector functions in macrophages. Adenovirus mediated transduction of the active form of IRF-7 into primary macrophages resulted in the production of type I IFN, upregulation of target genes including TRAIL and increased tumoricidal activity of macrophages; in contrast, the active form of IRF-3 led to induction of cell death. These studies indicate that IRF-7 transduced macrophages may be an attractive candidate for in vivo adoptive therapy of cancer.
Solis
Mayra
M
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, Montreal, Canada H3T 1E2.
Goubau
Delphine
D
Romieu-Mourez
Raphaëlle
R
Genin
Pierre
P
Civas
Ahmet
A
Hiscott
John
J
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D015967:Gene Expression Regulation, Viral; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology*; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D014161:Transduction, Genetic
D000970:Antineoplastic Agents; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha