Journal of Biological Chemistry
Volume 286, Issue 3, 21 January 2011, Pages 1786-1794
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RNA
The Interleukin 13 (IL-13) Pathway in Human Macrophages Is Modulated by MicroRNA-155 via Direct Targeting of Interleukin 13 Receptor α1 (IL13Rα1)*

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Macrophages play a central role in the balance and efficiency of the immune response and are at the interface between innate and adaptive immunity. Their phenotype is a delicate equilibrium between the M1 (classical, pro-Th1) and M2 (alternative, pro-Th2) profiles. This balance is regulated by cytokines such as interleukin 13 (IL-13), a typical pro-M2-Th2 cytokine that has been related to allergic disease and asthma. IL-13 binds to IL-13 receptor α1 (IL13Rα1), a component of the Type II IL-4 receptor, and exerts its effects by activating the transcription factor signal transducer and activator of transcription 6 (STAT6) through phosphorylation. MicroRNAs are short (∼22 nucleotide) inhibitory non-coding RNAs that block the translation or promote the degradation of their specific mRNA targets. By bioinformatics analysis, we found that microRNA-155 (miR-155) is predicted to target IL13Rα1. This suggested that miR-155 might be involved in the regulation of the M1/M2 balance in macrophages by modulating IL-13 effects. miR-155 has been implicated in the development of a healthy immune system and function as well as in the inflammatory pro-Th1/M1 immune profile. Here we have shown that in human macrophages, miR-155 directly targets IL13Rα1 and reduces the levels of IL13Rα1 protein, leading to diminished activation of STAT6. Finally we also demonstrate that miR-155 affects the IL-13-dependent regulation of several genes (SOCS1, DC-SIGN, CCL18, CD23, and SERPINE) involved in the establishment of an M2/pro-Th2 phenotype in macrophages. Our work shows a central role for miR-155 in determining the M2 phenotype in human macrophages.

Gene Expression
Gene Regulation
Immunology
Inflammation
Interleukin
Macrophage
MicroRNA
STAT Transcription Factor

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*

This work was supported by Medical Research Council (MRC) Grant G0801984 (to T. S.-E. and to F. L.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S9.