TLR

**Figure 2:** The signaling pathway for *TLR* is thought to be as outlined in the figure. LPS is lipo-polysaccharide, TLR is the toll like receptor, IRAK is interleukin-1 receptor accessory protein kinase, TRAF6 is tumour necrosis factor receptor associated factor, NIK is NF-kappa B inducing kinase, NF-kB is nuclear factor kappa b, I-kB is the inhibitory subunit of NF-kB, MyD88 is myeloid differentiation factor.
a) *TLR* has a leucine rich extracellular domain that binds to *LPS*. There is an intracellular domain that is homologous to the inter leukin 1 receptor.
b) Binding of *LPS*to the *TLR* results in oligomerisation and binding of the *TLR*s to an adaptor protein such as MyD88. This results in activation of IRAK and TRAF6.
c) Activated TRAF6 then activates NIK
d) Activated NIK phosphorylates the I-kB subunit of *NF- $\ensuremath{\kappa}$ B*. This exposes the nuclear localisation component of *NF- $\ensuremath{\kappa}$ B* which translocates to the nucleas, where it acts as a transcription factor for cytokines such as *IL-1* and *TNF- $\ensuremath{\alpha}$* .
$\begin{figure}\centering \includegraphics{tlr} \end{figure}$

Toll like receptors (TLR) are transmembrane proteins containing repeated leucine rich motifs in their extracellular domains, similar to other pattern recognition receptors of the innate immune system. The cytoplamic component is homologous to the interleukin-1 receptor (IL-1r). It is felt that the cytoplasmic component is responsible for activation of intracellular signalling.

Like IL-1r TLR triggers the activation of various transcription factors, include nuclear factor kappa B (NF- $\ensuremath{\kappa}$ B), which are involved in the expression of many pro-inflammatory cytokines.

The effect on NF- $\ensuremath{\kappa}$ B depends on exposure of a nuclear localisation motif which is obscured by an inhibitory subunit. The inhibitory subunit is phosphorylated which results in exposure of the nuclear localisation motif. Phosphorylation of the NF- $\ensuremath{\kappa}$ B inhibitory subunit is accomplised by NIK, which in turn is activated by binding of MyD88, IRAK, and TRAF6 to the cytoplasmic IL-1r like domain of the TLR. Activation of the IL-1r like domain can only occur after binding of LPS or peptidoglycan to the TLR.

So far about nine, members of the TLR family have been identified, they are named TLR1 to TLR9.

The TLR are expressed on cells involved in first line host defences such as macrophages, neutrophils, epithelial cells lining the gut and respiratory tract, dermal endothelial cells, B cells, T cells and Dendritic cells.