Members of the Toll-like receptor (TLR) family, named for the closely related Toll receptor in Drosophila, play a pivotal role in innate immune responses. TLRs recognize conserved motifs found in various pathogens and mediate defense responses. Triggering of the TLR pathway leads to the activation of NF-?B and subsequent regulation of immune and inflammatory genes. The TLRs and members of the IL-1 receptor family share a conserved stretch of approximately 200 amino acids known as the Toll/Interleukin-1 receptor (TIR) domain. Upon activation, TLRs associate with a number of cytoplasmic adaptor proteins containing TIR domains, including myeloid differentiation factor 88 (MyD88), MyD88-adaptor-like/TIR-associated protein (MAL/TIRAP), Toll-receptor-associated activator of interferon (TRIF), and Toll-receptor-associated molecule (TRAM). This association leads to the recruitment and activation of IRAK1 and IRAK4, which form a complex with TRAF6 to activate TAK1 and IKK. Activation of IKK leads to the degradation of I?B, which normally maintains NF-?B in an inactive state by sequestering it in the cytoplasm.
Toll-like receptor 6 (TLR6) heterodimerizes with TLR2 and is expressed on the cell surface where it recognizes fungal zymosan and bacterial lipoproteins. In addition, a heterodimer of TLR4 and TLR6 was recently shown to assemble downstream of CD36 signaling and contribute to sterile inflammation in response to CD36 ligands, including low-density lipoprotein and ?-amyloid.