Abstract
Toll/IL-1R-domain-containing adaptor-inducing IFN-β (TRIF) is an important adaptor for TLR3- and TLR4-mediated inflammatory signaling pathways. Recent studies have shown that TRIF plays a key role in vessel inflammation and atherosclerosis; however, the precise mechanisms are unclear. We investigated the mechanisms of the TRIF-regulated inflammatory response in RAW264.7 macrophages under oxidized low-density lipoprotein (ox-LDL) stimulation. Our data show that ox-LDL induces TRIF, miR-155, and BIC expression, activates the ERK1/2 and SOCS1-STAT3-NF-κB signaling pathways, and elevates the levels of IL-6 and TNF-α in RAW264.7 cells. Knockdown of TRIF using TRIF siRNA suppressed BIC, miR-155, IL-6, and TNF-α expression and inhibited the ERK1/2 and SOCS1-STAT3-NF-κB signaling pathways. Inhibition of ERK1/2 signaling also suppressed BIC and miR-155 expression. These findings suggest that TRIF plays an important role in regulating the ox-LDL-induced macrophage inflammatory response and that TRIF modulates the expression of BIC/miR-155 and the downstream SOCS1-STAT3-NF-κB signaling pathway via ERK1/2. Therefore, TRIF might be a novel therapeutic target for atherosclerosis.
MeSH terms
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / metabolism*
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Adaptor Proteins, Vesicular Transport / physiology
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Animals
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Gene Silencing
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Inflammation Mediators / metabolism
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Lipoproteins, LDL / pharmacology*
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MAP Kinase Signaling System*
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Macrophages / drug effects
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Macrophages / enzymology
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Macrophages / metabolism*
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Macrophages / physiology
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Mice
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MicroRNAs / drug effects
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MicroRNAs / metabolism*
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 1 / physiology
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mitogen-Activated Protein Kinase 3 / physiology
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NF-kappa B / metabolism
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RAW 264.7 Cells
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RNA Precursors / metabolism
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RNA, Small Interfering
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Suppressor of Cytokine Signaling 1 Protein / metabolism
Substances
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Adaptor Proteins, Vesicular Transport
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Inflammation Mediators
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Lipoproteins, LDL
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MicroRNAs
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Mirn155 microRNA, mouse
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NF-kappa B
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RNA Precursors
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RNA, Small Interfering
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STAT3 Transcription Factor
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Socs1 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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TICAM-1 protein, mouse
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oxidized low density lipoprotein
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Mapk1 protein, mouse
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3