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    Absence of MyD88 results in enhanced TLR3-dependent phosphorylation of IRF3 and increased IFN-(beta) and RANTES production

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    Authors
    Siednienko, Jakub
    Gajanayake, Thusitha
    Fitzgerald, Katherine A.
    Moynagh, Paul
    Miggin, Sinead M.
    UMass Chan Affiliations
    Department of Medicine, Division of Infectious Diseases and Immunology
    Document Type
    Journal Article
    Publication Date
    2011-02-21
    Keywords
    Myeloid Differentiation Factor 88
    Toll-Like Receptor 3
    Viral Proteins
    Interferon Regulatory Factors
    Immunology and Infectious Disease
    
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    Link to Full Text
    http://dx.doi.org/10.4049/jimmunol.1003093
    Abstract
    Toll-like receptors are a group of pattern-recognition receptors that play a crucial role in "danger" recognition and induction of the innate immune response against bacterial and viral infections. TLR3 has emerged as a key sensor of viral dsRNA, resulting in the induction of the anti-viral molecule, IFN-beta. Thus, a clearer understanding of the biological processes that modulate TLR3 signaling is essential. Previous studies have shown that the TLR adaptor, Mal/TIRAP, an activator of TLR4, inhibits TLR3-mediated IFN-beta induction through a mechanism involving IRF7. In this study, we sought to investigate whether the TLR adaptor, MyD88, an activator of all TLRs except TLR3, has the ability to modulate TLR3 signaling. Although MyD88 does not significantly affect TLR3 ligand-induced TNF-alpha induction, MyD88 negatively regulates TLR3-, but not TLR4-, mediated IFN-beta and RANTES production; this process is mechanistically distinct from that employed by Mal/TIRAP. We show that MyD88 inhibits IKKepsilon-, but not TBK1-, induced activation of IRF3. In doing so, MyD88 curtails TLR3 ligand-induced IFN-beta induction. The present study shows that while MyD88 activates all TLRs except TLR3, MyD88 also functions as a negative regulator of TLR3. Thus, MyD88 is essential in restricting TLR3 signaling, thereby protecting the host from unwanted immunopathologies associated with the excessive production of IFN-beta. Our study offers a new role for MyD88 in restricting TLR3 signaling through a hitherto unknown mechanism whereby MyD88 specifically impairs IKKepsilon-mediated induction of IRF3 and concomitant IFN-beta and RANTES production.
    Source
    J Immunol. 2011 Feb 15;186(4):2514-22. Epub 2011 Jan 19. Link to article on publisher's site
    DOI
    10.4049/jimmunol.1003093
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/34878
    PubMed ID
    21248248
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.4049/jimmunol.1003093
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