The attenuated inflammation of MPL is due to the lack of CD14-dependent tight dimerization of the TLR4/MD2 complex at the plasma membrane.
The attenuated inflammation of MPL is due to the lack of CD14-dependent tight dimerization of the TLR4/MD2 complex at the plasma membrane.
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MPL 炎症的减弱是由于质膜上 TLR4/MD2 复合物缺乏 CD14 依赖性紧密二聚化。
作者：
N. Tanimura;S. Saitoh;U. Ohto;Sachiko Akashi;Y. Fujimoto;K. Fukase;Toshiyuki Shimizu;K. Miyake
TLR 4/MD-2感知脂质A，在CD 14介导的TLR 4/MD-2内化到内体中后激活质膜上的MyD 88信号传导途径和TRIF信号传导途径。单磷酰脂质A（MPL）是脂质A的解毒衍生物，在激活MyD 88依赖性途径方面比脂质A弱。然而，关于MyD 88依赖性通路的减弱激活的潜在机制知之甚少。我们在此表明，与脂质A相比，MPL在诱导CD 14依赖性TLR 4/MD-2二聚化方面受损。TLR 4/MD-2二聚化受损可降低CD 14介导的TNFα产生。相比之下，MPL在CD 14非依赖性MyD 88依赖性TNFα产生和TRIF依赖性应答（包括细胞表面CD 86上调和IFNβ诱导）方面与脂质A相当。虽然CD 86上调依赖于TRIF信号传导，但其由质膜上的TLR 4/MD-2诱导。这些结果表明，减弱的MPL应答是由于质膜上的CD 14引发的应答，而不仅仅是由于MyD 88引发的应答，也就是说，MPL特异性地不能诱导选择性增强MyD 88介导的质膜上的应答的CD 14依赖性TLR 4/MD-2二聚化。
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 TNFα production. In contrast, MPL was comparable to lipid A in CD14-independent MyD88-dependent TNFα production and TRIF-dependent responses including cell surface CD86 up-regulation and IFNβ 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.