Absence of MyD88 results in enhanced TLR3-dependent phosphorylation of IRF3 and increased IFN-(beta) and RANTES production
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2011-02-21Keywords
Myeloid Differentiation Factor 88Toll-Like Receptor 3
Viral Proteins
Interferon Regulatory Factors
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
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 siteDOI
10.4049/jimmunol.1003093Permanent Link to this Item
http://hdl.handle.net/20.500.14038/34878PubMed ID
21248248Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.1003093