ArticleThe Journal of biological chemistry2016
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.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 19 citations in OpenAlex.
- Article
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- Lysosomal trafficking regulator restricts intracellular growth ofFrontiers in cellular and infection microbiology · 2023Article
- Toll-Like Receptor 3 (TLR3) Is Engaged in the Intracellular Survival of the Protozoan ParasiteInfection and immunity · 2022Article
- COVID-19 and hypertension: Is there a role for dsRNA and activation of Toll-like receptor 3?Vascular pharmacology · 2021Article
- Toll-like receptor 3 (TLR3) regulation mechanisms and roles in antiviral innate immune responses.Journal of Zhejiang University. Science. B · 2021Review
- Mucosal immunity and tRNA, tRF, and tiRNA.Journal of molecular medicine (Berlin, Germany) · 2021Review
- Exploiting somatic piRNAs inLife science alliance · 2020Article
- Immunostimulating RNA Delivered by P1500 PEGylated Cationic Liposomes Limits Influenza Infection in C57Bl/6 Mice.Pharmaceutics · 2020Article
- Depletion of RIPK1 in hepatocytes exacerbates liver damage in fulminant viral hepatitis.Cell death & disease · 2019Article
- The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis.Immunity · 2018Article
- Pure mechanistic analysis of additive neuroprotective effects between baicalin and jasminoidin in ischemic stroke mice.Acta pharmacologica Sinica · 2018Article
- Type I Interferon Supports Inducible Nitric Oxide Synthase in Murine Hepatoma Cells and Hepatocytes and during Experimental Acetaminophen-Induced Liver Damage.Frontiers in immunology · 2017Article
- Pathogenesis of Alcohol-Associated Liver Disease.Journal of clinical and experimental hepatologyReview
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
The sensing of double-stranded RNA (dsRNA) in the liver is important for antiviral defenses but can also contribute to sterile inflammation during liver injury. Hepatocytes are often the target of viral infection and are easily injured by inflammatory insults. Here we sought to establish the pathways involved in the production of type I interferons (IFN-I) in response to extracellular poly(I:C), a dsRNA mimetic, in hepatocytes. This was of interest because hepatocytes are long-lived and, unlike most immune cells that readily die after activation with dsRNA, are not viewed as cells with robust antimicrobial capacity. We found that poly(I:C) leads to rapid up-regulation of inducible nitric oxide synthase (iNOS), double-stranded RNA-dependent protein kinase (PKR), and Src. The production of IFN-β was dependent on iNOS, PKR, and Src and partially dependent on TLR3/Trif. iNOS and Src up-regulation was partially dependent on TLR3/Trif but entirely dependent on PKR. The phosphorylation of TLR3 on tyrosine 759 was shown to increase in parallel to IFN-β production in an iNOS- and Src-dependent manner, and Src was found to directly interact with TLR3 in the endosomal compartment of poly(I:C)-treated cells. Furthermore, we identified a robust NO/cGMP/PKG-dependent feedforward pathway for the amplification of iNOS expression. These data identify iNOS/NO as an integral component of IFN-β production in response to dsRNA in hepatocytes in a pathway that involves the coordinated activities of TLR3/Trif and PKR.
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