Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21
Nature immunology, 2010•nature.com
The tumor suppressor PDCD4 is a proinflammatory protein that promotes activation of the
transcription factor NF-κB 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-κB 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 …
transcription factor NF-κB 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-κB 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 …
Abstract
The tumor suppressor PDCD4 is a proinflammatory protein that promotes activation of the transcription factor NF-κB 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-κB 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-κB. Transfection of cells with a miR-21 precursor blocked NF-κB 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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