Mechanism of up-regulation of human Toll-like receptor 3 secondary to infection of measles virus-attenuated strains.
PolyI:C, a synthetic double-stranded (ds)RNA, and viruses act on cells to induce IFN-beta which is a key molecule for anti-viral response. Although dsRNA is a virus-specific signature and a ligand for human Toll-like receptor 3 (TLR3), largely uncharacterized multiple pathways associate virus-mediated IFN-beta induction. Here, we demonstrated that laboratory-adapted but not wild-type strains of measles virus (MV) up-regulated TLR3 expression both in dendritic cells and epithelial cell line A549. The kinetics experiments with the laboratory MV strain revealed that TLR3 was induced late compared to IFN-beta and required new protein synthesis. Furthermore, neutralizing antibodies against IFN-beta or IFNAR (Interferon-alpha/beta receptor) suppressed MV-induced TLR3 induction, indicating that type I IFN, IFN-alpha/beta, is critical for MV-mediated TLR3 induction. Yet, a recently identified virus-inducible IFN, the IFN-lambda, did not contribute to TLR3 expression. A virus-responsive element that up-regulates TLR3 was identified in the TLR3-promoter region by reporter gene experiments. The ISRE, a recently reported site for IFN-beta induction, but not STAT binding site, located around -30bp of TLR3 promoter responded to MV to induce TLR3 expression. This further indicates the importance of type I IFN for TLR3 up-regulation in the case of viral infection. In HeLa and MRC5 cells, augmented production of IFN-beta was observed in response to dsRNA when TLR3 had been induced beforehand. Thus, the MV-induced expression of TLR3 may reflect amplified IFN production that plays a part in host defense to viral infection.
Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Japan.
Masako
M
Tanabe
Mitsue
M
Kurita-Taniguchi
Kaoru
K
Takeuchi
Makoto
M
Takeda
Minoru
M
Ayata
Hisashi
H
Ogura
Misako
M
Matsumoto
Tsukasa
T
Seya
D002460:Cell Line; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D016899:Interferon-beta / Q000276:immunology* / Q000378:metabolism*; D008457:Measles / Q000276:immunology / Q000378:metabolism*; D008459:Measles virus / Q000145:classification / Q000276:immunology / Q000472:pathogenicity*; D008562:Membrane Glycoproteins / Q000145:classification / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000145:classification / Q000276:immunology / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D015854:Up-Regulation / Q000502:physiology*; D014613:Vaccines, Attenuated
D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014613:Vaccines, Attenuated; D016899:Interferon-beta