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Biopharmaceutics Research Group, Airways Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom
Posttranscriptional regulation of gene expression by microRNAs (miRNAs) has been implicated in the regulation of chronic physiological and pathological responses. In this report, we demonstrate that changes in the expression of miRNAs can also regulate acute inflammatory responses in human lung alveolar epithelial cells. Thus, stimulation with IL-1β results in a rapid time- and concentration-dependent increase in miRNA-146a and, to a lesser extent, miRNA-146b expression, although these increases were only observed at high IL-1β concentration. Examination of miRNA function by overexpression and inhibition showed that increased miRNA-146a expression negatively regulated the release of the proinflammatory chemokines IL-8 and RANTES. Subsequent examination of the mechanism demonstrated that the action of miRNA-146a was mediated at the translational level and not through the down-regulation of proteins involved in the IL-1β signaling pathway or chemokine transcription or secretion. Overall, these studies indicate that rapid increase in miRNA-146a expression provides a novel mechanism for the negative regulation of severe inflammation during the innate immune response.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Biotechnology and Biological Sciences Research Council (BB/C508234/1 to S.A.M.). H.M.L.-S. is supported by a National Heart and Lung Institute Ph.D studentship, and M.M.P., A.E.W., and M.A.L. are supported by the Wellcome Trust (076111).
2 Address correspondence and reprint requests to Dr. Mark A. Lindsay, Biopharmaceutics Research Group, Airways Disease, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, U.K. E-mail address: m.lindsay{at}imperial.ac.uk
3 Abbreviations used in this paper: TIR, Toll/IL-1R; ARE, AU-rich element; IRAK1, IL-1R-associated kinase 1; miRNA, microRNA; MRE, miRNA recognition element; RNAi, RNA interference; TRAF6, TNFR-associated factor 6; UTR, untranslated region.
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