Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21

Frederick J Sheedy; Eva Palsson-McDermott; Elizabeth J Hennessy; Cara Martin; John J O'Leary; Qingguo Ruan; Derek S Johnson; Youhai Chen; Luke A J O'Neill

doi:10.1038/ni.1828

Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21

Nat Immunol. 2010 Feb;11(2):141-7. doi: 10.1038/ni.1828. Epub 2009 Nov 29.

Authors

Frederick J Sheedy¹, Eva Palsson-McDermott, Elizabeth J Hennessy, Cara Martin, John J O'Leary, Qingguo Ruan, Derek S Johnson, Youhai Chen, Luke A J O'Neill

Affiliation

¹ School of Biochemistry & Immunology, Trinity College, Dublin, Ireland.

PMID: 19946272
DOI: 10.1038/ni.1828

Abstract

The tumor suppressor PDCD4 is a proinflammatory protein that promotes activation of the transcription factor NF-kappaB and suppresses interleukin 10 (IL-10). Here we found that mice deficient in PDCD4 were protected from lipopolysaccharide (LPS)-induced death. The induction of NF-kappaB and IL-6 by LPS required PDCD4, whereas LPS enhanced IL-10 induction in cells lacking PDCD4. Treatment of human peripheral blood mononuclear cells with LPS resulted in lower PDCD4 expression, which was due to induction of the microRNA miR-21 via the adaptor MyD88 and NF-kappaB. Transfection of cells with a miR-21 precursor blocked NF-kappaB activity and promoted IL-10 production in response to LPS, whereas transfection with antisense oligonucleotides to miR-21 or targeted protection of the miR-21 site in Pdcd4 mRNA had the opposite effect. Thus, miR-21 regulates PDCD4 expression after LPS stimulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins / immunology*
Apoptosis Regulatory Proteins / metabolism
Blotting, Western
Enzyme-Linked Immunosorbent Assay
Gene Expression Regulation / immunology*
Humans
Immunoprecipitation
Interleukin-10 / immunology
Interleukin-10 / metabolism
Interleukin-6 / immunology
Interleukin-6 / metabolism
Lipopolysaccharides / immunology
Lipopolysaccharides / pharmacology
Membrane Glycoproteins / immunology
Membrane Glycoproteins / metabolism
Mice
MicroRNAs / immunology*
MicroRNAs / metabolism
NF-kappa B / immunology
NF-kappa B / metabolism
Polymerase Chain Reaction
RNA-Binding Proteins / immunology*
RNA-Binding Proteins / metabolism
Receptors, Interleukin-1 / immunology
Receptors, Interleukin-1 / metabolism
Signal Transduction / immunology*
Toll-Like Receptor 4 / immunology*
Toll-Like Receptor 4 / metabolism
Transfection

Substances

Apoptosis Regulatory Proteins
Interleukin-6
Lipopolysaccharides
MIRN21 microRNA, human
Membrane Glycoproteins
MicroRNAs
NF-kappa B
PDCD4 protein, human
RNA-Binding Proteins
Receptors, Interleukin-1
TIRAP protein, human
Toll-Like Receptor 4
Interleukin-10