| First Author | Vila-del Sol V | Year | 2008 |
| Journal | J Immunol | Volume | 181 |
| Issue | 7 | Pages | 4461-70 |
| PubMed ID | 18802049 | Mgi Jnum | J:141300 |
| Mgi Id | MGI:3818096 | Doi | 10.4049/jimmunol.181.7.4461 |
| Citation | Vila-del Sol V, et al. (2008) IFN-gamma-Induced TNF-alpha expression is regulated by interferon regulatory factors 1 and 8 in mouse macrophages. J Immunol 181(7):4461-70 |
| abstractText | We have previously described that IFN-gamma induces cyclooxygenase 2 and inducible NO synthase expression by a mechanism that involved endogenously produced TNF-alpha. In this study, we report that TNF-alpha production is induced by IFN-gamma treatment in the murine macrophage cell line RAW 264.7. TNF-alpha mRNA levels are increased in cells treated with IFN-gamma in a time-dependent manner and IFN-gamma also increased human TNF-alpha promoter-dependent transcription. Two regions in the TNF-alpha promoter seem to be responsible for the IFN-gamma response: a distal region between -1311 and -615 bp of the human TNF-alpha promoter, and a proximal region located between -95 and -36 bp upstream of the transcriptional start. In contrast, IFN-gamma 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-alpha promoter. There is a correlation between the regions of the TNF-alpha promoter responsible of the transcriptional activation elicited by IRF-1 and IRF-8 and those required for IFN-gamma response. In addition, IRF-1 and IRF-8 are recruited to the TNF-alpha promoter in IFN-gamma-treated RAW 264.7 cells, as demonstrated by chromatin immunoprecipitation assays. Moreover, overexpression of IRF-1 and IRF-8 induces TNF-alpha production in unstimulated RAW 264.7 macrophages, comparable to the production of TNF-alpha elicited by IFN-gamma stimulation, and silencing of IRF-1 and/or IRF-8 with specific small interfering RNAs, decreases IFN-gamma-elicited TNF-alpha production. In summary, IFN-gamma treatment induces TNF-alpha expression at transcriptional level requiring the coordinate action of IRF-1 and IRF-8. |
