Abstract
Interleukin-10 (IL-10) mediates an anti-inflammatory response that constrains immune responses and limits inflammation-associated pathology. IL-10 does so, in part, by selectively inhibiting pro-inflammatory cytokine and chemokine expression induced in macrophages in response to Toll-like receptor (TLR) signaling. The IL-10-mediated anti-inflammatory response is executed through the activation of STAT3 leading to induction of target genes referred to as IL-10-induced genes. As miRNAs have emerged as important negative regulators of gene expression in various systems, we sought to address whether the IL-10-mediated anti-inflammatory response acts through regulated expression of miRNA genes. Using quantitative PCR-based arrays, we examined 140 miRNA genes with putative roles in inflammation for changes in expression in response to IL-10 and lipopoly-saccharide (LPS) in primary mouse macrophages. IL-10 stimulation resulted in the inhibition of miR-147 expression induced in response to LPS, while having a potentiating effect on the induction of miR-455. miR-147 is the second TLR-induced miRNA, in addition to miR-155, identified to be counter-regulated by IL-10. Its suppression by IL-10 suggests that miR-147 may have an unknown pro-inflammatory function in TLR-triggered macrophages. The results extend the notion that IL-10 selectively regulates expression of miRNA genes, and that miRNA-mediated pathways are a component of the IL-10-mediated anti-inflammatory response.
Highlights
Cells of the innate immune system—including macrophages, dendritic cells, and neutrophils—recognize andHow to cite this paper: Cardwell, L.N. and Weaver, B.K. (2014) IL-10 Inhibits LPS-Induced Expression of miR-147 in Murine Macrophages
pattern recognition receptors (PRRs) are a diverse group of danger-signal sensors that fall into three major protein families: the membranebound Toll-like receptors (TLRs), the cytosolic NOD-like receptors (NLRs), and the cytosolic RIG-I-like receptors (RLRs)
Stimulation with LPS led to an increase in Tnip3 expression, but this was largely due to the autocrine effects of IL-10 working in concert with the LPS/Toll-like Receptor 4 (TLR4) signals, as shown by reduced induction when the neutralizing IL-10R1 antibody was added along with LPS
Summary
Cells of the innate immune system—including macrophages, dendritic cells, and neutrophils—recognize andHow to cite this paper: Cardwell, L.N. and Weaver, B.K. (2014) IL-10 Inhibits LPS-Induced Expression of miR-147 in Murine Macrophages. K. Weaver respond to microbial pathogens using an array of germ-line encoded pattern recognition receptors (PRRs) [1]-[3]. PRRs bind to specific cognate pathogen-associated molecular patterns (PAMPs) and signal for the activation of transcription factors that induce expression of numerous pro-inflammatory genes, including cytokines and chemokines, that promote the host inflammatory response [4]-[6]. This is exemplified by Toll-like Receptor 4 (TLR4) and its recognition of the prototypical PAMP lipopolysaccharide (LPS) produced by gramnegative bacteria [7] [8]. The anti-inflammatory cytokine interleukin-10 (IL-10) has become recognized as a central player in this regulation and resolution of inflammation
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