Overview of Toll-like Receptors
The TLRs owe their name to a closely related receptor called Toll, first identified in Drosophila. The first member of the Toll family was identified in Drosophila in 1988 during a screen for embryonic polarity genes. In Drosophila, Toll receptors cause an induction of innate immune responses by first linking to an adaptor tube, which is a functional homolog of mammalian MyD88. This tube binds to kinase Pelle, a homologue of IRAK, and after a cascade of reactions leads to transcription of genes that modulate and mediate activation of antimicrobial pathways that directly kill the pathogen.
Stimulation of TLRs by pathogens leads to expression of several genes involved in immune responses through a number of signaling pathways. Activated pathways include the NF-kB pathway (IkBa phosphorylation, translocation of NF-kB p65 to the nucleus), mitogen activated protein kinases p38, Jun-N-terminal kinase (JNK), and the interferon pathway.
While TLR-mediated signaling pathways are still being elucidated, a number of specific molecules are known to be involved. These include adapter molecules such as MyD88, MyD88 adapter-like (Mal), also known as Toll/IL-1R (TIR) domain containing adaptor protein (TIRAP), and TIR domain-containing adapter inducing interferon (TRIF), also known as TICAM1. Other key signaling proteins include IL-1 receptor associated kinases (IRAKs) such as IRAK1, 2, and 4, transforming growth factor kinase (TAK-1), IkB kinases (IKKs), and TRAFs (TNF receptor associated factors).
TLR-mediated Signaling Pathway Inhibitors
Inhibitors of molecules downstream of Toll-like Receptors have the potential to mediate and down regulate the effect of TLR activation. This feature may allow further characterization of TLR signaling, and also may be of therapeutic significance in the treatment of endotoxic shock and some cancers.