Abstract
MicroRNAs are known to control TLR activation in phagocytes. We have shown that leukotriene (LT) B4 (LTB4) positively regulates macrophage MyD88 expression by decreasing suppressor of cytokine signaling-1 (SOCS-1) mRNA stability. In this study, we investigated the possibility that LTB4 control of MyD88 expression involves the generation of microRNAs. Our data show that LTB4, via its receptor B leukotriene receptor 1 (BLT1) and Gαi signaling, increased macrophage expression of inflammatory microRNAs, including miR-155, miR-146b, and miR-125b. LTB4-mediated miR-155 generation was attributable to activating protein-1 activation. Furthermore, macrophage transfection with antagomirs against miR-155 and miR-146b prevented both the LTB4-mediated decrease in SOCS-1 and increase in MyD88. Transfection with miR-155 and miR-146b mimics decreased SOCS-1 levels, increased MyD88 expression, and restored TLR4 responsiveness in both wild type and LT-deficient macrophages. To our knowledge, our data unveil a heretofore unrecognized role for the GPCR BLT1 in controlling expression of microRNAs that regulate MyD88-dependent activation of macrophages.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Female
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GTP-Binding Protein alpha Subunits / genetics
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GTP-Binding Protein alpha Subunits / immunology
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology*
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / pathology
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Leukotriene B4 / genetics
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Leukotriene B4 / immunology*
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Macrophage Activation*
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Macrophages, Peritoneal / immunology*
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Macrophages, Peritoneal / pathology
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Mice
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Mice, Knockout
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MicroRNAs / genetics
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MicroRNAs / immunology*
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / immunology*
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Receptors, Leukotriene B4 / genetics
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Receptors, Leukotriene B4 / immunology
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Signal Transduction / genetics
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Signal Transduction / immunology
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins / genetics
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Suppressor of Cytokine Signaling Proteins / immunology
Substances
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GTP-Binding Protein alpha Subunits
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Ltb4r1 protein, mouse
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MicroRNAs
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Receptors, Leukotriene B4
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Socs1 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Leukotriene B4