期刊
JOURNAL OF IMMUNOLOGY
卷 175, 期 10, 页码 6465-6472出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.175.10.6465
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资金
- NCRR NIH HHS [RR14466] Funding Source: Medline
- NIAID NIH HHS [AI 52455] Funding Source: Medline
- NIGMS NIH HHS [R01 GM54060] Funding Source: Medline
The detection of Gram-negative LPS depends upon the proper function of the TLR4-MD-2 receptor complex in immune cells. TLR4 is the signal transduction component of the LPS receptor, whereas MD-2 is the endotoxin-binding unit. MD-2 appears to activate TLR4 when bound to TLR4 and ligated by LIPS. Only the monomeric form of MD-2 was found to bind LIPS and only monomeric MD-2 interacts with TLR4. Monomeric MD-2 binds TLR4 with an apparent K-d of 12 nM; this binding avidity was unaltered in the presence of endotoxin. E5564, an LPS antagonist, appears to inhibit cellular activation by competitively preventing the binding of LPS to MD-2. Depletion of endogenous soluble MD-2 from human serum, with an immobilized TLR4 fusion protein, abrogated TLR4-mediated LPS responses. By determining the concentration of added-back MD-2 that restored normal LPS responsiveness, the concentration of MD-2 was estimated to be similar to 50 nM. Similarly, purified TLR4-Fc fusion protein, when added to the supernatants of TLR4-expressing cells in culture, inhibited the interaction of MD-2 with TLR4, thus preventing LIPS stimulation. The ability to inhibit the effects of LIPS as a result of the binding of TLR4-Fc or E5564 to MD-2 highlights MD-2 as the logical target for drug therapies designed to pharmacologically intervene against endotoxin-induced disease.
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