Review Article

Toll-Like Receptors, Tissue Injury, and Tumourigenesis

Figure 2

Toll-like receptor (TLR) signalling is mediated by at least two distinct pathways. After recognition of a pathogen-specific molecular pattern, TLRs are capable of differentially activating distinct downstream signalling events via different cofactors and adaptor proteins mediating diverse immune responses [1]. The MyD88-dependent TLR signalling pathway is activated via the conserved, cytoplasmic TIR domain, which provides a scaffold for recruitment of the adaptor molecule MyD88 and serine/threonine kinases of the IL-1R-associated kinase (IRAK) family. Following IRAK autophosphorylation, the TRAF6 adaptor protein interacts and induces translocation of the transcription factor NF-κB to the nucleus, resulting in transcriptional activation of genes encoding cytokines and chemokines (TNF-α, NO, COX-2, SOCS (for “suppressor of cytokine signalling”), IP-10, IFN-b and IL-1, 6, 8, 10, 12). In addition, expression of proteins involved in apoptosis and production of adherent and costimulative molecules such as ICAM1, occur. Moreover, TLRs bridge the signalling pathway via ECSIT (for “evolutionarily conserved signalling intermediate in Toll pathways”) to TRAF6 for p42/p44 mitogen-activated protein kinase (MAPK) kinase (MKK), p38, and JNK in response to specific bacterial products [2]. The MyD88-independent TLR signalling pathway is activated via TIRAP and results in activation of the dsRNA-binding protein kinase PKR. This protein has been proposed to be a central downstream component of both the TIRAP- and MyD88-dependent signalling pathways and could mediate potential crosstalk between them. The MyD88-independent pathway appears to utilise both IFN-regulatory factor 3 (IRF3) and NF-κB, and results in the expression of IFN-g-inducible genes including IP-10.
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