The Role of Ets2 Transcription Factor in the Induction of MicroRNA-155 (miR-155) by Lipopolysaccharide and Its Targeting by Interleukin-10

• Published in: The Journal of biological chemistry Vol. 289; no. 7; pp. 4316 - 4325
• Main Authors: Quinn, Susan R., Mangan, Niamh E., Caffrey, Brian E., Gantier, Michael P., Williams, Bryan R.G., Hertzog, Paul J., McCoy, Claire E., O'Neill, Luke A.J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.02.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Line; Ets Family Transcription Factor; Ets2; Humans; Immunology; Inflammation - chemically induced; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Interleukin; Interleukin 10; Interleukin-10 - biosynthesis; Interleukin-10 - genetics; Lipopolysaccharide (LPS); Lipopolysaccharides - toxicity; Mice; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - genetics; miR-155; Proto-Oncogene Protein c-ets-2 - genetics; Proto-Oncogene Protein c-ets-2 - metabolism; Response Elements; SHIP1; TLR4; Toll-like Receptors (TLR); Toll-like Receptors (TLR); Ets Family Transcription Factor; MicroRNA; Interleukin; SHIP1; miR-155; Interleukin 10; TLR4; Lipopolysaccharide (LPS); Ets2
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.522730

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. miR-155 is strongly induced by LPS, a response inhibited by IL-10. The Ets2 transcription factor is required for induction of miR-155 by LPS. IL-10 can subsequently decrease miR-155 via suppression of Ets2. Ets2 is an important transcription factor for regulation of miR-155. This study reports a detailed mechanism of induction of miR-155 and provides a new means of inhibition for IL-10 via suppression of Ets2.