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Andrei Medvedev, Wenji Piao, Sang Hoon Rhee, Haiyan Chen, Subhendu Basu, Larry M Wahl, Matthew J Fenton, Stefanie N Vogel, ROLE OF TLR4 TYROSINE PHOSPHORYLATION IN SIGNAL TRANSDUCTION AND ENDOTOXIN TOLERANCE (89.2), The Journal of Immunology, Volume 178, Issue 1_Supplement, April 2007, Pages S148–S149, https://doi.org/10.4049/jimmunol.178.Supp.89.2
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Abstract
This study examined if tyrosine phosphorylation of TLR4 is required for signaling. Introduction of the P712H mutation into the TIR domain of constitutively-active mouse ΔTLR4 and mutation of the homologous P714 in human CD4-TLR4 rendered them signaling-incompetent and blocked TLR4 tyrosine phosphorylation. Y674A and Y680A mutations within the TIR domains of CD4-TLR4 impaired its ability to elicit phosphorylation of p38 and JNK, IκB-α degradation, and activation of NF-κB and RANTES reporters. Full-length human TLR4 expressing Y674A or Y680A mutations showed suppressed LPS-inducible cell activation that correlated with altered MyD88-TLR4 interactions, increased association with a short IRAK-1 isoform, and decreased levels of activated IRAK-1 in complex with TLR4. Pretreatment of HEK293/TLR4/MD-2 cells with protein tyrosine kinase or Src kinase inhibitors suppressed LPS-driven TLR4 tyrosine phosphorylation, p38 and NF-κB activation. Induction of endotoxin tolerance markedly suppressed LPS-mediated TLR4 tyrosine phosphorylation and recruitment of Lyn kinase to TLR4, but did not affect TLR4-MD-2 interactions. These data demonstrate that TLR4 tyrosine phosphorylation is important for signaling and is impaired in endotoxin tolerance, and suggest involvement of Lyn kinase in these processes.
This study was supported by NIH grants AI-059524 (AEM), AI-057490 and AI-44936 (SNV).
