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Nucleic Acids Research Advance Access published online on July 13, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp577
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Silencing of microRNA-155 in mice during acute inflammatory response leads to derepression of c/ebp Beta and down-regulation of G-CSF

Jesper Worm1, Jan Stenvang1,2, Andreas Petri1, Klaus Stensgaard Frederiksen3, Susanna Obad1, Joacim Elmén1, Maj Hedtjärn1, Ellen Marie Straarup1, Jens Bo Hansen1 and Sakari Kauppinen1,2,*

1Santaris Pharma, Kogle Allé 6, DK-2970 Hørsholm, 2Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N and 3Novo Nordisk A/S, Novo Allé 3, DK-2880 Bagsværd, Denmark

*To whom correspondence should be addressed. Tel: +45 45 17 98 38; Fax: +45 45 17 98 98; Email: sk{at}santaris.com

Received December 3, 2008. Revised June 4, 2009. Accepted June 22, 2009.

microRNA-155 (miR-155) has been implicated as a central regulator of the immune system, but its function during acute inflammatory responses is still poorly understood. Here we show that exposure of cultured macrophages and mice to lipopolysaccharide (LPS) leads to up-regulation of miR-155 and that the transcription factor c/ebp Beta is a direct target of miR-155. Interestingly, expression profiling of LPS-stimulated macrophages combined with overexpression and silencing of miR-155 in murine macrophages and human monocytic cells uncovered marked changes in the expression of granulocyte colony-stimulating factor (G-CSF), a central regulator of granulopoiesis during inflammatory responses. Consistent with these data, we show that silencing of miR-155 in LPS-treated mice by systemically administered LNA-antimiR results in derepression of the c/ebp Beta isoforms and down-regulation of G-CSF expression in mouse splenocytes. Finally, we report for the first time on miR-155 silencing in vivo in a mouse inflammation model, which underscores the potential of miR-155 antagonists in the development of novel therapeutics for treatment of chronic inflammatory diseases.


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