Myeloid Differentiation Factor 88–Dependent and –Independent Pathways in Toll‐Like Receptor Signaling

Toll-like receptors (TLRs) play an essential role in the detection of invading pathogens in the body. Individual TLRs recognize distinct components derived from pathogens, which is followed by cytokine production. The TLR family harbors extracellular leucine-rich repeat domains and a cytoplasmic domain that is homologous to that of the interleukin (IL)-1 receptor (IL-1R) family. After stimulation, TLR recruits IL-1R-associated kinase via adaptor myeloid differentiation factor 88 (MyD88) and induces activation of NF-kappaB and mitogen-activated protein kinases. Cytokine production in response to each TLR ligand is completely abrogated in MyD88-deficient cells, which indicates that MyD88 is an essential shared signaling molecule in the IL-1R/Toll family. The TLR4 signal has an MyD88-independent pathway that is involved in induction of type I interferons (IFNs) and IFN-inducible genes via IFN regulatory factor-3 activation. A recently identified adaptor molecule, Toll-IL receptor domain-containing adaptor protein/MyD88 adaptor-like, may participate in the MyD88-independent pathway.