Figure 1.

TLR signalling pathways. For simplicity reasons the signalling pathways induced by toll-like receptor (TLR)4, which utilises all four known adaptor proteins, is shown. Following stimulation and dimerisation, the IL-1R and TLR signalling pathways, with the exception of TLR3, recruit the adaptor molecule MyD88 and induce nuclear factor (NF)-κB and mitogen-activated protein kinases (MAPKs) through IL-1R associated kinase (IRAK)-4, IRAK-1 and TNF receptor associated factor (TRAF)-6. In addition, a MyD88-independent signalling pathway is utilised by TLR3 and TLR4, which depends on the adaptor molecule TRIF (TIR-domain-containing adapter-inducing interferon-β) and leads to the induction of interferon regulatory factors (IRFs) and a late activation of NF-κB. Signalling through TLR4 results in phosphoprylation and activation of protein tyrosine kinases (TKs). The Tec family member Btk interacts with the Toll/IL-1 receptor (TIR) domains of TLRs, MyD88 and Mal (MyD88 adaptor like protein). Once activated, Btk phoshporylates Mal and activates NF-κB and/or p38 MAPK. Src family kinases (SFKs; for example, Hck) are known to function upstream of both Pyk2 and Syk kinases, respectively, in TLR signalling. TLRs mediate phosphatidylinositol-3-kinase (PI3K) activation that suppresses p38 MAPK and NF-κB. Inhibition of these signalling cascades by PI3K is possibly mediated by protein kinase B (PKB), and limits the production of inflammatory cytokines. IKK = IkappaB kinase; RANTES, Regulated on activation, normal T expressed and secreted; TBK, TANK-binding kinase; TNF, tumour necrosis factor; TRAM, TRIF-related adaptor molecule.

Drexler et al. Arthritis Research & Therapy 2008 10:216   doi:10.1186/ar2481
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