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Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells
B. Aouar, D. Kovarova, S. Letard, A. Font-Haro, J. Florentin, J. Weber, D. Durantel, L. Chaperot, J. Plumas, K. Trejbalova, J. Hejnar, JA. Nunès, D. Olive, P. Dubreuil, I. Hirsch, R. Stranska,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
NLK
Directory of Open Access Journals
od 2006
Free Medical Journals
od 2006
Public Library of Science (PLoS)
od 2006
PubMed Central
od 2006
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od 2006
ProQuest Central
od 2006-12-01
Open Access Digital Library
od 2006-01-01
Open Access Digital Library
od 2006-01-01
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od 2006-10-01
Medline Complete (EBSCOhost)
od 2008-01-01
Nursing & Allied Health Database (ProQuest)
od 2006-12-01
Health & Medicine (ProQuest)
od 2006-12-01
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od 2006-12-01
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od 2006
- MeSH
- cytokiny metabolismus MeSH
- dendritické buňky účinky léků metabolismus MeSH
- fosforylace účinky léků MeSH
- inhibitory proteinkinas farmakologie MeSH
- kinasa Syk antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- přirozená imunita MeSH
- signální transdukce účinky léků fyziologie MeSH
- toll-like receptory agonisté metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Crosslinking of regulatory immunoreceptors (RR), such as BDCA-2 (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses production of type-I interferon (IFN)-α/β and other cytokines in response to Toll-like receptor (TLR) 7/9 ligands. This cytokine-inhibitory pathway is mediated by spleen tyrosine kinase (Syk) associated with the ITAM-containing adapter of RR. Here we demonstrate by pharmacological targeting of Syk that in addition to the negative regulation of TLR7/9 signaling via RR, Syk also positively regulates the TLR7/9 pathway in human pDCs. Novel highly specific Syk inhibitor AB8779 suppressed IFN-α, TNF-α and IL-6 production induced by TLR7/9 agonists in primary pDCs and in the pDC cell line GEN2.2. Triggering of TLR9 or RR signaling induced a differential kinetics of phosphorylation at Y352 and Y525/526 of Syk and a differential sensitivity to AB8779. Consistent with the different roles of Syk in TLR7/9 and RR signaling, a concentration of AB8779 insufficient to block TLR7/9 signaling still released the block of IFN-α production triggered via the RR pathway, including that induced by hepatitis B and C viruses. Thus, pharmacological targeting of Syk partially restored the main pDC function-IFN-α production. Opposing roles of Syk in TLR7/9 and RR pathways may regulate the innate immune response to weaken inflammation reaction.
Centre de Recherche en Cancérologie de Lyon Inserm U1052 CNRS UMR5286 Lyon France
Institute of Molecular Genetics Czech Academy of Sciences Prague Czech Republic
Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czech Republic
UJF INSERM U823 University Grenoble Alpes EFS Rhone Alpes Grenoble France
Citace poskytuje Crossref.org
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