Tlr Signalling

The intracellular signalling pathways of mammalian TLRs, IL-1R and IL-18R are mediated by their homologous TIR-domain. In general, these receptors stimulate the production of inflammatory cytokines and/or maturation of DCs, a feature required for successful initiation of adaptive immunity [64-66], Induction of direct antimicrobial defence activity can also result from TLR activation [67], A general TLR signalling pathway is depicted in Fig. 2A, although several divergent pathways and differences in usage of intracellular components have emerged from recent studies (for example, Fig. 2B).

In the common TIR signalling pathway, the adapter MyD88 is crucial in initiating a signalling cascade culminating in activation of mitogen-activated protein (MAP) kinases, translocation of NF-kB, and production of inflammatory cytokines. The TIR signalling pathways are reviewed in [64,65], MyD88 associates with TLRs through TIR-domain interactions, and recruits a family of IL-1R associated kinases (IRAK) in complex with the adaptor protein, Tollip. The family of IRAK proteins consists of two active kinases, IRAKI and 4, and two inactive kinases, IRAK2 and M [68], Interaction of MyD88 and IRAKI/4 through their death domains leads to the phosphorylation of IRAKI, a process that may be controlled by IRAK4 [68]. IRAK4 is essential for TLR signalling, whereas, the related protein, IRAKM, negatively regulates TLR signalling [68-70]. Activated IRAK 1/4 recruits a downstream adapter, TRAF6, that is subsequently ubiq-uitinated. Ubiquitinated TRAF6 then interacts with two adapter proteins TAB-1 and TAB-2, and a kinase called TAK-1. Activation of TAK-1 triggers two downstream pathways: It directly activates I-kB kinases that phosphorylate 1-kB, a binding partner of the transcription factor NF-kB. This phosphorylation leads to the degradation of I-kB and the translocation of NF-kB to the nucleus. TAK-1 also activates the MAP kinase pathway, and the integration of NF-kB and MAP kinase activation eventually results in production of inflammatory cytokines like TNFa and IL-6 [64,65],

The general pathway described above has a great many subtleties. For example, TIRAP, an adaptor protein, is crucial in MyD88-dependent signalling by TLR2/1/6 and TLR4, but not by TLR3, TLR5, TLR7, TLR9, IL1R and IL18R [71,72], Other signalling molecules such as the GTPase, racl, and the phosphatidylinositol-3 kinase, PI3K, have also been implicated in the TLR pathway, but the role of these molecules needs to be clarified [73], A new TIR-containing adaptor, TRIF, was recently reported [74], MyD88, TIRAP and TRIF make up a fascinating area of research, as the interplay between these adaptors may be important in generating diversity of TLR signalling.

The adaptor, MyD88, has a critical role in host defence [64], However, TLR4 and TLR3 also signal via one or more MyD88 (and TIRAP) independent pathways [46,75], One such pathway leads to the expression of I FN[3 that stimulates a variety of genes such as IP-10 and GARG-16, apparently via an autocrine loop [64,71,76], TLR3 and TLR4 mediated increase of co-stimulatory molecules on dendritic cells can also occur independently of MyD88 and TIRAP [64,71,77],

Microbe 1

Microbe 2

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