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• W2077881218 startingPage "532" @default.
• W2077881218 abstract "Within hours after its initiation, the severe systemic inflammatory response of sepsis shifts to an adaptive anti-inflammatory state with coincident immunosuppression. This anti-inflammatory phenotype is characterized by diminished proinflammatory cytokine gene expression in response to toll-like receptor (TLR) stimulation with bacterial endotoxin/lipopolysaccharide (LPS), also known as endotoxin tolerance/adaptation. Our and other studies have established that gene-specific reprogramming following TLR4 responses independently represses transcription and translation of proinflammatory genes such as tumor necrosis factor alpha (TNFα). We also previously demonstrated that TNFα and interleukin (IL)-6 mRNA translation is repressed in endotoxin-adapted THP-1 human monocytes by an miRNA-based mechanism involving the argonaute family protein argonaute 2 (Ago2). Here, we further define the molecular nature of reprogramming translation by showing that TLR4-induced microRNA-146 promotes a feed-forward loop that modifies the subcellular localization of the RNA-binding protein RBM4 (RNA-binding motif protein 4) and promotes its interaction with Ago2. This interaction results in the assembly of a translation-repressor complex that disrupts TNFα and IL-6 cytokine synthesis in endotoxin-adapted THP-1 monocytes. This novel molecular path prevents the phosphorylation of RBM4 on serine-309 by p38 MAPK (mitogen-activated protein kinase), which leads to RBM4 accumulation in the cytosol and interaction with Ago2. We further find that microRNA-146a knockdown by antagomirs or protein phosphatase inhibition by okadaic acid increases p38 MAPK phosphorylation and results in RBM4 serine-309 phosphorylation and nuclear relocalization, which disrupts RBM4 and Ago2 interactions and restores TLR4-dependent synthesis of TNFα and IL-6. We conclude that miR-146a has a diverse and critical role in limiting an excessive acute inflammatory reaction." @default.
• W2077881218 created "2016-06-24" @default.
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• W2077881218 date "2013-07-30" @default.
• W2077881218 modified "2023-10-10" @default.
• W2077881218 title "MicroRNA‐146a and RBM4 form a negative feed‐forward loop that disrupts cytokine mRNA translation following TLR4 responses in human THP‐1 monocytes" @default.
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• W2077881218 doi "https://doi.org/10.1038/icb.2013.37" @default.
• W2077881218 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3770753" @default.
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