| First Author | Tanimura N | Year | 2014 |
| Journal | Int Immunol | Volume | 26 |
| Issue | 6 | Pages | 307-14 |
| PubMed ID | 24380872 | Mgi Jnum | J:222669 |
| Mgi Id | MGI:5645195 | Doi | 10.1093/intimm/dxt071 |
| Citation | Tanimura N, et al. (2014) The attenuated inflammation of MPL is due to the lack of CD14-dependent tight dimerization of the TLR4/MD2 complex at the plasma membrane. Int Immunol 26(6):307-14 |
| abstractText | 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 TNFalpha production. In contrast, MPL was comparable to lipid A in CD14-independent MyD88-dependent TNFalpha production and TRIF-dependent responses including cell surface CD86 up-regulation and IFNbeta 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. |
