Journal
INTERNATIONAL IMMUNOLOGY
Volume 26, Issue 6, Pages 307-314Publisher
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxt071
Keywords
CD14; LBP; MPL; TLR4/MD-2
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology for Program of Japan Initiative for Global Research Network on Infectious Diseases [10005010]
- Japan Science and Technology Agency for Japanese-Korean Cooperative Program on Basic Medical Research
- JSPS [PD1810234, RPD2540043]
- [20659074]
- [21117002]
- [24790463]
- Grants-in-Aid for Scientific Research [21117002, 23241074, 23590564, 25670189, 24117706] Funding Source: KAKEN
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TLR4/MD-2 senses lipid A, activating the MyD88-signaling pathway on the plasma membrane and the TRIF-signaling pathway after CD14-mediated TLR4/MD-2 internalization into endosomes. Monophosphoryl lipid A (MPL), a detoxified derivative of lipid A, is weaker than lipid A in activating the MyD88-dependent pathway. Little is known, however, about mechanisms underlying the attenuated activation of MyD88-dependent pathways. We here show that MPL was impaired in induction of CD14-dependent TLR4/MD-2 dimerization compared with lipid A. Impaired TLR4/MD-2 dimerization decreased CD14-mediated TNF alpha production. In contrast, MPL was comparable to lipid A in CD14-independent MyD88-dependent TNF alpha production and TRIF-dependent responses including cell surface CD86 up-regulation and IFN beta induction. Although CD86 up-regulation is dependent on TRIF signaling, it was induced by TLR4/MD-2 at the plasma membrane. These results revealed that the attenuated MPL responses were due to CD14-initiated responses at the plasma membrane, but not just to responses initiated by MyD88, that is, MPL was specifically unable to induce CD14-dependent TLR4/MD-2 dimerization that selectively enhances MyD88-mediated responses at the plasma membrane.
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