Negative Regulation of TLR4 Via Targeting of the Proinflammatory Tumor Suppressor PDCD4 by the MicroRNA MiR-21

Overview

Journal Nat Immunol

Date 2009 Dec 1

PMID 19946272

Citations 522

Authors

Frederick J Sheedy

Eva Palsson-McDermott

Elizabeth J Hennessy

Cara Martin

John J OLeary

Qingguo Ruan

Derek S Johnson

Youhai Chen

Luke A J ONeill

Affiliations

Soon will be listed here.

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.

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