Signal Transduction Pathways Activated by the IL-1 Receptor/toll-like Receptor Superfamily

Toll-like receptors (TLRs) are an important point of first contact between host and microbe, and once activated generate signals which culminate in the induction of genes important for host defence. TLRs respond to different microbial products, and the signalling pathways activated are very similar to that generated by the pro-inflammatory cytokine interleukin-1 (IL-1). This is because the Type I IL-1 receptor and TLRs are highly homologous in their cytosolic portions, possessing a Toll/IL-1 receptor (TIR) domain. Signals triggered include the important transcription factor NF-kappa B and two MAP kinases, p38 and Jun N-terminal kinase. Receptor-proximal proteins involved include the adapter MyD88, IRAK, IRAK-2, Tollip, TRAF6 and TAK-1. These latter two proteins need to be ubiquitinated in order to be active. Differences between signals generated by TLRs are emerging, with TLR-4 signalling requiring an additional adapter termed MyD88-adapter-like (Mal), which may regulate the expression of genes specific for the response required to eliminate infection by Gram-negative bacteria. Future studies on TLR signalling may reveal hitherto unsuspected specificities in the innate immune response to infection.