1. Mechanistic role of microRNA-146a in endotoxin-induced differential cross-regulation of TLR signaling.
- Author
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Nahid MA, Satoh M, and Chan EK
- Subjects
- Animals, Bacteroidaceae Infections immunology, Bacteroidaceae Infections metabolism, Cell Line, Tumor, Cytokines antagonists & inhibitors, Cytokines biosynthesis, Escherichia coli Infections immunology, Escherichia coli Infections metabolism, Female, Humans, Immunity, Innate, Inflammation Mediators antagonists & inhibitors, Inflammation Mediators metabolism, Ligands, Mice, Mice, Inbred C57BL, MicroRNAs antagonists & inhibitors, MicroRNAs biosynthesis, Monocytes immunology, Monocytes metabolism, Staphylococcal Infections immunology, Staphylococcal Infections metabolism, Toll-Like Receptors physiology, Immune Tolerance, Lipopolysaccharides toxicity, MicroRNAs physiology, Signal Transduction immunology, Toll-Like Receptors metabolism
- Abstract
Human TLRs are critical sensors for microbial components leading to the production of proinflammatory cytokines that are controlled by various mechanisms. Monocytes pretreated with LPS exhibit a state of hyporesponsiveness, referred to as cross-tolerance, to both homologous and heterologous ligands, which play a broader role in innate immunity. To date, LPS-induced cross-tolerance has not been examined regarding microRNA expression kinetics. In this study, THP-1 monocytes treated with various inflammatory ligands showed a continuous amplification of microRNA (miR)-146a over 24 h that is inversely correlated to TNF-α production. In contrast, inhibition of miR-146a showed a reciprocal effect. Thus, the characteristic upregulation of miR-146a in LPS-exposed THP-1 monocytes was studied for cross-tolerance. Strikingly, in LPS-tolerized THP-1 monocytes, only miR-146a showed a continuous overexpression, suggesting its crucial role in cross-tolerance. Similarly, peptidoglycan-primed THP-1 cells showed homologous tolerance associated with miR-146a upregulation. Subsequently, interchangeable differential cross-regulation was observed among non-LPS ligands. TLR2 and TLR5 ligands showed both homologous and heterologous tolerance correlated to miR-146a overexpression. More importantly, inflammatory responses to TLR4, TLR2, and TLR5 ligands were reduced due to knockdown of miR-146a targets IL-1R-associated kinase 1 or TNFR-associated factor 6, suggesting the regulatory effect of miR-146a on these TLRs signaling. Transfection of miR-146a into THP-1 cells caused reduction of TNF-α production, mimicking LPS-induced cross-tolerance. Aside from individual ligands, a whole bacterial challenge in LPS-primed THP-1 monocytes was accompanied by less TNF-α production, which is conversely correlated to miR-146a expression. Our studies have thus demonstrated that miR-146a plays a crucial role for in vitro monocytic cell-based endotoxin-induced cross-tolerance.
- Published
- 2011
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