ArticleThe Journal of biological chemistry2014
The inducible nitric-oxide synthase (iNOS)/Src axis mediates Toll-like receptor 3 tyrosine 759 phosphorylation and enhances its signal transduction, leading to interferon-β synthesis in macrophages.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- Current review on inducible nitric oxide synthase and Src tyrosine kinase inhibitors as disease-modifiers in preclinical models of epilepsy.Histology and histopathology · 2026Review
- Non-Targeting shRNA-Encoded Plasmid DNA Enhances Protective Immunity Through RIDD-RIG-I Signaling Pathway in the Zika Virus Animal Model.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Sevelamer Ameliorates Early Cirrhosis and Inhibits Its Progression towards Hepatocellular Carcinoma in a Diethylnitrosamine-induced Rat Model.Journal of cancer prevention · 2025Article
- Anti-Inflammatory Properties of the Citrus Flavonoid Diosmetin: An Updated Review of Experimental Models.Molecules (Basel, Switzerland) · 2024Review
- Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy.Neurobiology of disease · 2021Article
- Diosmetin Attenuates Akt Signaling Pathway by Modulating Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB)/Inducible Nitric Oxide Synthase (iNOS) in Streptozotocin (STZ)-Induced Diabetic Nephropathy Mice.Medical science monitor : international medical journal of experimental and clinical research · 2018Article
- Post-translational regulation of antiviral innate signaling.European journal of immunology · 2017Review
- TLR9 stability and signaling are regulated by phosphorylation and cell stress.Journal of leukocyte biology · 2016Article
- Interferon β (IFN-β) Production during the Double-stranded RNA (dsRNA) Response in Hepatocytes Involves Coordinated and Feedforward Signaling through Toll-like Receptor 3 (TLR3), RNA-dependent Protein Kinase (PKR), Inducible Nitric Oxide Synthase (iNOS), and Src Protein.The Journal of biological chemistry · 2016Article
- Src is required for migration, phagocytosis, and interferon beta production in Toll-like receptor-engaged macrophages.BioMedicine · 2016Article
- Novel Types of Small RNA Exhibit Sequence- and Target-dependent Angiogenesis Suppression Without Activation of Toll-like Receptor 3 in an Age-related Macular Degeneration (AMD) Mouse Model.Molecular therapy. Nucleic acids · 2015Article
- Transfected poly(I:C) activates different dsRNA receptors, leading to apoptosis or immunoadjuvant response in androgen-independent prostate cancer cells.The Journal of biological chemistry · 2015Article
- Tyrosine phosphorylation in Toll-like receptor signaling.Cytokine & growth factor reviews · 2014Review
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Double-stranded RNA (dsRNA) induces phosphorylation of Toll-like receptor 3 (TLR3) at tyrosine 759 and subsequently triggers signaling pathways to promote interferon-β (IFN-β) production. In this study, we found that dsRNA stimulation induces biphasic TLR3 Tyr-759 phosphorylation in macrophages. In addition to the immediate TLR3 Tyr-759 phosphorylation, we identified a second wave of Tyr-759 phosphorylation accompanied by an increase of both Src and ifn-β transcription in the later phase of dsRNA stimulation. Interestingly, Src phosphorylated TLR3 Tyr-759 in vitro and in vivo. However, knockdown of Src abolished the late phase of TLR3 Tyr-759 phosphorylation and decreased the nuclear accumulation of interferon regulatory factors 3 and 7 (IRF3 and -7) and IFN-β production. Reintroduction of Src restored all of these molecular changes. Notably, via down-regulation of Src, dsRNA-elicited TLR3 Tyr-759 phosphorylation, the nuclear accumulation of IRF3/IRF7, and IFN-β generation were inhibited in inducible nitric-oxide synthase (iNOS)-null macrophages. TLR3 knockdown destabilized Src and reduced the nuclear level of IRF3/IRF7 and IFN-β production in macrophages exposed to LPS (a TLR4 ligand known to induce Src and IFN-β expression). Ectopic expression of wild type TLR3, but not its 759-phenylalanine mutant, restored Src activity and ifn-β transcription. Taken together, these results suggested an essential role of the iNOS/Src/TLR3 axis in IFN-β production in macrophages.
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