TLR受体研究进展_协和医科大学何维教授精彩讲演.ppt

TLR9 was recently identified as the third member of the mammalian TLR family member responsible for mediating the recognition of bacterial DNA. The molecular mechanism responsible for the ability to discriminate bacterial DNA from human DNA remained obscure until recent discoveries with TLR9. TLR9-DN mutants had no TNF, IL-12, IL-6 and interferon-γ response on exposure to oligonucleotides containing CpG motifs found in microbial DNA. Moreover, TLR9 knockout mice are refractory to lethal shock from synthetic oligonucleotides bearing unmethylated CpG motifs that rapidly induce refractory hypotension and lethality in wild-type mice. The intracellular signaling pathways responsible for CpG DNA immunostimulation share some similarities with other pattern recognition molecules such as TLR4. TLR-9: Toll-like Receptor 9 TLR5 is the Toll-like molecule that recognizes flagellin from both Gram-positive and Gram-negative bacteria. Activation of the receptor mobilizes NF-kB and stimulates TNF-a production. Murine TLR5 lies within a locus that is associated with susceptibility to Salmonella. Flagellin is critical for bacterial motility and is therefore conserved. Thus it fits well the profile of a relatively invariant PAMP. TLR-5: Toll-like Receptor 5 TLR3 Toll-like receptor 3 recognizes double-stranded RNA (dsRNA). This molecular pattern is associated with viral infection, because it is produced by most viruses at some point during their replication. TLR3-deficient mice showed reduced responses to polycytidylic acid (poly(I:C)), resistance to the lethal effect of poly(I:C) when s ensitized with D-galactosamine, and reduced production of inflammatory cytokines. TLR-3: Toll-like Receptor 3 TLR1 is expressed ubiquitously and at rather high levels. TLR6 is not as well understood as other members of the TLR family. Studies with TLR6- and TLR2-deficient mice have shown that TLR2 is essential for the response to bacterial lipoproteins triacylated at the N-terminus c