IL-10-induced microRNA-187 negatively regulates TNF-α, IL-6, and IL-12p40 production in TLR4-stimulated monocytes

Marzia Rossato, Graziella Curtale, Nicola Tamassia, Monica Castellucci, Laura Mori, Sara Gasperini, Barbara Mariotti, Mariacristina De Luca, Massimiliano Mirolo, Marco A. Cassatella, Massimo Locati, Flavia Bazzoni

Research output: Contribution to journalArticle

Abstract

IL-10 is a potent anti-inflammatory molecule that, in phagocytes, negatively targets cytokine expression at transcriptional and posttranscriptional levels. Posttranscriptional checkpoints also represent the specific target of a recently discovered, evolutionary conserved class of small silencing RNAs known as "microRNAs" (miRNAs), which display the peculiar function of negatively regulating mRNA processing, stability, and translation. In this study, we report that activation of primary human monocytes up-regulates the expression of miR-187 both in vitro and in vivo. Accordingly, we identify miR-187 as an IL-10-dependent miRNA playing a role in IL-10-mediated suppression of TNF-α, IL-6, and the p40 subunit of IL-12 (IL-12p40) produced by primary human monocytes following activation of Toll-like receptor 4 (TLR4). Ectopic expression of miR-187 consistently and selectively reduces TNFα, IL-6, and IL-12p40 produced by LPS-activated monocytes. Conversely, the production of LPS-induced TNF-α, IL-6, and IL-12p40 is increased significantly when miR-187 expression is silenced. Our data demonstrate that miR-187 directly targets TNF-α mRNA stability and translation and indirectly decreases IL-6 and IL-12p40 expression via down-modulation of IκBζ, a master regulator of the transcription of these latter two cytokines. These results uncover an miRNA-mediated pathway controlling cytokine expression and demonstrate a central role of miR-187 in the physiological regulation of IL-10-driven anti-inflammatory responses.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number45
DOIs
Publication statusPublished - Nov 6 2012

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Interleukin-12 Subunit p40
Toll-Like Receptor 4
MicroRNAs
Interleukin-10
Monocytes
Interleukin-6
RNA Stability
Protein Biosynthesis
Cytokines
Anti-Inflammatory Agents
Interleukin-12
Phagocytes
RNA Interference
Up-Regulation

ASJC Scopus subject areas

  • General

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IL-10-induced microRNA-187 negatively regulates TNF-α, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. / Rossato, Marzia; Curtale, Graziella; Tamassia, Nicola; Castellucci, Monica; Mori, Laura; Gasperini, Sara; Mariotti, Barbara; De Luca, Mariacristina; Mirolo, Massimiliano; Cassatella, Marco A.; Locati, Massimo; Bazzoni, Flavia.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 45, 06.11.2012.

Research output: Contribution to journalArticle

Rossato, M, Curtale, G, Tamassia, N, Castellucci, M, Mori, L, Gasperini, S, Mariotti, B, De Luca, M, Mirolo, M, Cassatella, MA, Locati, M & Bazzoni, F 2012, 'IL-10-induced microRNA-187 negatively regulates TNF-α, IL-6, and IL-12p40 production in TLR4-stimulated monocytes', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 45. https://doi.org/10.1073/pnas.1209100109
Rossato, Marzia ; Curtale, Graziella ; Tamassia, Nicola ; Castellucci, Monica ; Mori, Laura ; Gasperini, Sara ; Mariotti, Barbara ; De Luca, Mariacristina ; Mirolo, Massimiliano ; Cassatella, Marco A. ; Locati, Massimo ; Bazzoni, Flavia. / IL-10-induced microRNA-187 negatively regulates TNF-α, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 45.
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AU - Rossato, Marzia

AU - Curtale, Graziella

AU - Tamassia, Nicola

AU - Castellucci, Monica

AU - Mori, Laura

AU - Gasperini, Sara

AU - Mariotti, Barbara

AU - De Luca, Mariacristina

AU - Mirolo, Massimiliano

AU - Cassatella, Marco A.

AU - Locati, Massimo

AU - Bazzoni, Flavia

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