| Summary: | 碩士 === 國立陽明大學 === 微生物及免疫學研究所 === 97 === Toll-like receptors (TLRs) play very important roles in inflammatory response. They recognize pathogen-associated molecular patterns (PAMPs) and induce cells to produce inflammatory cytokines, chemokines and interferons. Upon LPS stimulation, TLR4 activates both MyD88-dependent (early stage) and TRIF-dependent pathway (late stage), but the mechanism involved in regulation of these two pathways remains unclear. Recently, the key adaptor protein of TNFR1 signaling, TRADD (TNF receptor-associated death domain), had been reported involved not only in TNFR1 signaling but also in TLR3 signaling through the TRIF-dependent pathway. Whether TRADD plays roles in TLR4-mediated signaling remains an unsolved question. In this study, by using biochemical approach, we demonstrated the interaction between TRADD and the signaling components of TLR4 (such as MyD88, Mal, TIR domain of receptor and RIP). It was well demonstrated that TRADD plays a positive role in TRIF-dependent signaling. Here we focus on dissecting the role of TRADD in the early stage MyD88-dependent signals. With the treatment of Dynasore (an inhibitor of endocytosis which blocks TRIF-dependent signals), LPS induce an increased NF-�羠-mediated signal and enhanced cytokines production in TRADD deficient cells than in wild-type cells. Taken together, our results reveal a novel negative regulatory role of TRADD in Mal-MyD88 related signaling-mediated by TLR4 and it is presumed that TRADD may play role as a regulator in the interchange of TLR4 signaling.
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