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-Induced TNF-
Expression Is Regulated by Interferon Regulatory Factors 1 and 8 in Mouse Macrophages1Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, c/Nicolás Cabrera, 1 Campus Cantoblanco, Universidad Autónoma de Madrid, Madrid, Spain
We have previously described that IFN-
induces cyclooxygenase 2 and inducible NO synthase expression by a mechanism that involved endogenously produced TNF-
. In this study, we report that TNF- production is induced by IFN- treatment in the murine macrophage cell line RAW 264.7. TNF- mRNA levels are increased in cells treated with IFN- in a time-dependent manner and IFN- also increased human TNF- promoter-dependent transcription. Two regions in the TNF- promoter seem to be responsible for the IFN- response: a distal region between –1311 and –615 bp of the human TNF- promoter, and a proximal region located between –95 and –36 bp upstream of the transcriptional start. In contrast, IFN- stimulation induces the expression of the transcription factors IRF-1 and IRF-8. Overexpression of these transcription factors produces an increase in the transcriptional activity of the human TNF- promoter. There is a correlation between the regions of the TNF- promoter responsible of the transcriptional activation elicited by IRF-1 and IRF-8 and those required for IFN- response. In addition, IRF-1 and IRF-8 are recruited to the TNF- promoter in IFN--treated RAW 264.7 cells, as demonstrated by chromatin immunoprecipitation assays. Moreover, overexpression of IRF-1 and IRF-8 induces TNF- production in unstimulated RAW 264.7 macrophages, comparable to the production of TNF- elicited by IFN- stimulation, and silencing of IRF-1 and/or IRF-8 with specific small interfering RNAs, decreases IFN--elicited TNF- production. In summary, IFN- treatment induces TNF- expression at transcriptional level requiring the coordinate action of IRF-1 and IRF-8.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by grants from Programa Nacional de Salud of Spain (SAF2004-05104, SAF2005-02220, SAF2007-61716), Fondo de Investigaciones Sanitarias PI040993, Red Temática de Investigación Cooperativa Sanitaria ISCIII (RED RIS G04/173, RED RECAVA C03/01 and RED RICET RD06/0021/0016), Comunidad Autónoma de Madrid (SAL/2001/2004 and S2006/SAL-0159), the Sixth European Union Framework Programme European Commission (Integrated project EICOSANOX, LSH-CT-2004-005033 and MAIN network of excellence), and the Fundación Ramón Areces (to M.F.).
2 Current address: Grupo de Neurobiología del Desarrollo, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos, Toledo, Spain
3 Address correspondence and reprint requests to Dr. Manuel Fresno, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain. E-mail address: mfresno{at}cbm.uam.es
4 Abbreviations used in this paper: iNOS, inducible NO synthase; IRF, IFN regulatory factor; COX-2, cyclooxygenase-2; siRNA, small interfering RNA.
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