Structure-function studies on low-toxicity TLR4 simulation

摘要: TLR4 stimulation by lipopolysaccharide (LPS) can cause both MAL/MyD88-and TRAM/TRIF-dependent signaling events. Monophosphoryl Lipid A (MPLA), a low toxicity derivative of endotoxic LPS enhances antibody responses as well as T cell expansion and recall responses against antigens without causing excessive inflammatory side effects. Previously we proposed that TRIF-biased activation of TLR4 by MPLA is responsible for its reduced toxicity while retaining potent adjuvant effects. However, some TRIF-associated genes such as MCP1 are only weakly expressed and some MyD88-associated inflammatory and anti-inflammatory cytokines such as TNFα and IL10 are strongly activated after MPLA stimulation despite weak NF-κB but strong IRF3 activation. We now report that synthetic derivatives of MPLA (sMLA) retained TRIF-bias as compared to synthetic diphosphoryl Lipid A (sDLA), indicating a change in …