Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21.
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.
Sheedy
Frederick J
FJ
School of Biochemistry & Immunology, Trinity College, Dublin, Ireland.
Palsson-McDermott
Eva
E
Hennessy
Elizabeth J
EJ
Martin
Cara
C
O'Leary
John J
JJ
Ruan
Qingguo
Q
Johnson
Derek S
DS
Chen
Youhai
Y
O'Neill
Luke A J
LA
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D047468:Immunoprecipitation; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D016133:Polymerase Chain Reaction; D016601:RNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; C524940:MIRN21 microRNA, human; D008562:Membrane Glycoproteins; D035683:MicroRNAs; D016328:NF-kappa B; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D051197:Toll-Like Receptor 4; D016753:Interleukin-10