The role of Ets2 transcription factor in the induction of microRNA-155 by LPS, and its targeting by IL-10 [Gene Regulation]

December 20th, 2013 by Quinn, S. R., Mangan, N. E., Caffrey, B. E., Gantier, M. P., Williams, B. R. G., Hertzog, P. J., McCoy, C. E., O'Neill, L. A. J.

MicroRNA-155 (miR-155) is highly expressed in many cancers such as B cell lymphomas and myeloid leukaemia, 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.