期刊
JOURNAL OF IMMUNOLOGY
卷 190, 期 8, 页码 4005-4013出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1202911
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资金
- National Institutes of Health [AI-075284, CA143379, HL-090775]
- Scholar in Clinical Research from the Leukemia and Lymphoma Society
MicroRNAs (miRs) have emerged as critical modulators of immune responses, but little is known about their transcriptional regulation and tissue specificity. miR-142 is specifically expressed in hematopoietic tissues and plays an important role in regulating immunity. In this study we identified the key transcriptional elements for regulation of miR-142 and its impact on TLR4-mediated expression of IL-6. The PU.1, C/EBP beta, and Runx1 transcription factor binding sites are conserved and constitutively occupied by the respective transcription factors in the miR-142 gene promoter only in the hematopoietic cells. Specific knockdown experiments in hematopoietic cells and rescue experiments in nonhematopoietic cells show that PU.1 is critical for miR-142 gene expression and that it synergizes with Runx1, C/EBP beta, and CBF beta. Furthermore, TLR4 stimulation enhanced miR-155 whereas experiments with knockdown and mimic expression of miR-155 demonstrated that miR-155 negatively regulates miR-142-3p expression by targeting PU.1. Thus, TLR4 stimulation represses PU.1, resulting in downregulation of miR-142 and increased expression of IL-6. These results collectively reveal the direct cis-acting sequences of miR-142 specific promoter and that transcription factor PU.1 is necessary for its exclusive expression in hematopoietic cells and regulation of IL-6. The Journal of Immunology, 2013, 190: 4005-4013.
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