Natural Products with Toll-Like Receptor 4 Antagonist Activity

Figure 1

TLR4 intracellular signaling pathways. TLR4 signaling is induced by interaction with the specific ligand (e.g., LPS). In detail, LPS binding to MD-2 promotes dimerization of TLR4/MD-2 with the recruitment of intracellular adaptor proteins, MyD88 and TIRAP (MyD88-dependent pathway) or TRIF and TRAM (MyD88-independent pathway). In MyD88-dependent pathway, there is the recruitment and activation of IRAKs and TRAF6, inducing TAK1 activation. TAK1 coupling to the IKK complex and NEMO leads to IkB phosphorylation and nuclear translocation of NF-κB. TAK1-dependent activation of MKKs promotes AP-1 transcription factor induction. In MyD88-independent pathway TRIF and TRAM adaptor proteins are involved in the activation of TRAF3 and, downstream, in the induction of TBK1 and IKKε, needed for the activation of the transcription factor IRF3.