The study of the interference of soluble TLR4-TIR domain on TNF receptor-mediated signaling

• Main Authors: Yi-Hsiu WU, 吳逸修
• Other Authors: Nien-Jung Chen
• Format: Others
• Language: en_US
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/30812307453547381747

碩士 === 國立陽明大學 === 微生物及免疫學研究所 === 98 === Tumor necrosis factor (TNF) is a multifunctional cytokine that involves in inflammation and cell death. It is also served as a drug target to many inflammatory diseases. TNFR1 is the major receptor mediates the activation of NF-?羠 to promote inflammation and also the activation of caspase-8 for apoptosis upon TNF stimulation. Activation of pattern-recognition receptors during infection often leads to the massive induction of TNF. Toll-like receptors, for example, play important roles in pathogen-induced inflammation and are also mediated by the activation of NF-?羠. Due to the similarities of downstream signals mediated by TLR and TNFR1, more and more evidences showed signaling cross-talk between them. Here, we report that overexpression of TIR domain (intracellular domain of TLR4) inhibits not only TLR4-, but also TNF-mediated NF-?羠 activation. To the contrary, ectopic expression of TLR4 TIR domain cannot rescue TRADD-induced cell death. Biochemical evidences demonstrate the association between TIR domain and downstream adaptor proteins of TNFR1 (such as TRADD, FADD and RIP). Furthermore, TNF-induced IL-6 production is dramatically boosted in the macrophages pre-stimulated with LPS indicates that TLR-TNF crosstalk may modulate TNF responses during pathogen infection. Taken all, we reveal a novel cross-talk effect of TLR-mediated signals to facilitate the subsequent NF-?羠 activation of TNFR1. TIR domain or mimics may serve as new targets for designing new strategy of inhibiting both TLR and TNFR1-related inflammation.