Synergistic regulation of the human interleukin-12 p40 promoter by NFkappaB and Ets transcription factors in Epstein-Barr virus-transformed B cells and macrophages.
Monocytes/macrophages produce interleukin-12 (IL-12) in response to pathogenic stimulation, whereas most Epstein-Barr virus-transformed (EBV+) B cells constitutively secrete IL-12. The molecular mechanism regulating the constitutive IL-12 gene expression in EBV+ B cells has not been addressed. In this study, using the EBV+ B cell line RPMI-8866, we localized to the human IL-12 p40 promoter two essential cis elements, the NFkappaB site and the Ets site. The NFkappaB site was shown to interact with members of the NFkappaB family: p50 and c-Rel. The Ets site constitutively bound a multi-component Ets-2-containing complex. While the NFkappaB and Ets sites appear equally critical for inducible p40 promoter activity in macrophage cell lines, NFkappaB plays a more dominant role in the constitutive p40 promoter activity in EBV+ B cells. Transient expression of Ets-2 and c-Rel in B, T, and monocytic cell lines synergistically activated the IL-12 p40 promoter, apparently overcoming the requirement for cell type- or stimulant-specific transcription factors. These data provide new evidence that full activation of the human IL-12 p40 promoter may result primarily from the interplay between NFkappaB and Ets family members.
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Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104, USA.
Savio
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Trinchieri
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D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology; D001665:Binding Sites; D002472:Cell Transformation, Viral; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis*; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel; D012097:Repressor Proteins; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C107465:ERF protein, human; C494069:ETS2 protein, human; D016328:NF-kappa B; D009687:Nuclear Proteins; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D018664:Interleukin-12