title: The role of Ets2 transcription factor in the induction of microRNA-155 (miR-155) by lipopolysaccharide and its targeting by interleukin-10.
abstract: MicroRNA-155 (miR-155) is highly expressed in many cancers such as B cell lymphomas and myeloid leukemia and inflammatory disorders such as rheumatoid arthritis, atopic dermatitis, and multiple sclerosis. The role of miR-155 as both a promoter of inflammation and an oncogenic agent provides a clear need for miR-155 itself to be stringently regulated. We therefore investigated the transcriptional regulation of miR-155 in response to the respective pro- and anti-inflammatory mediators LPS and IL-10. Bioinformatic analysis revealed Ets binding sites on the miR-155 promoter, and we found that Ets2 is critical for miR-155 induction by LPS. Truncation and mutational analysis of the miR-155 promoter confirmed the role of the Ets2 binding site proximal to the transcription start site for LPS responsiveness. We observed increased binding of Ets2 to the miR-155 promoter and Ets2 deficient mice displayed decreased induction of miR-155 in response to LPS. IL-10 inhibited the induction of Ets2 mRNA and protein by LPS, thereby decreasing Ets2 function on the pri-155 promoter. We have thus identified Ets2 as a key novel regulator in both the positive and negative control of miR-155 in the inflammatory response.
authors.affiliation: From the School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Quinn
authors.forename: Niamh E
authors.initials: NE
authors.lastname: Mangan
authors.forename: Brian E
authors.initials: BE
authors.lastname: Caffrey
authors.forename: Michael P
authors.initials: MP
authors.lastname: Gantier
authors.forename: Bryan R G
authors.initials: BR
authors.lastname: Williams
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hertzog
authors.forename: Claire E
authors.initials: CE
authors.lastname: McCoy
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements
chemical_list: C494069:ETS2 protein, human; C494070:Ets2 protein, mouse; C508609:IL10 protein, human; C556062:IL10 protein, mouse; D008070:Lipopolysaccharides; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D050787:Proto-Oncogene Protein c-ets-2; D016753:Interleukin-10
keywords: Ets Family Transcription Factor; Ets2; Interleukin; Interleukin 10; Lipopolysaccharide (LPS); MicroRNA; SHIP1; TLR4; Toll-like Receptors (TLR); miR-155