Ligand-induced TLR dimerization is predicted to bring the TIR domains of the cytoplasmic tails of each protein close to one another. This is followed by recruitment of TIR domain-containing adaptor proteins, which facilitate the recruitment and activation of various protein kinases, leading to the activation of different transcription factors. The major transcription factors that are activated by TLR signaling pathways are nuclear factor kB (NF-kB), activation protein 1 (AP-1), interferon response factor 3 (IRF3), and IRF7. NF-kB and AP-1 stimulate the expression of genes encoding many of the molecules required for inflammatory responses including inflammatory cytokines (e.g., TNF and IL-1), chemokines (e.g., CCL2 and CXCL8), and endothelial adhesion molecules (e.g., E-selectin) (discussed later). IRF3 and IRF7 promote production of type I interferons (IFN-a and IFN-P), important for anti-viral innate immune responses.
Different combinations of adaptors and signaling intermediates are used by different TLRs, which is the basis for common and unique downstream effects of the TLRs. For example, cell surface TLRs that engage the adaptor MyD88 lead to NF-kB activation, and TLR signaling that uses the adaptor called TRIF (TIR domain-containing adaptor inducing IFN-P) leads to IRF3 activation. All TLRs except TLR3 signal through MyD88 and are therefore capable of activating NF-kB and inducing an inflammatory response. TLR3 signals through TRIF and therefore activates IRF3 and induces expression of type I interferons. TLR4 signals through both MyD88 and TRIF and is able to induce both types of responses. Endosomal TLRs 7 and 9, which are most highly expressed in plasmacytoid dendritic cells, signal through a MyD88-dependent, TRIF-independent pathway that activates both NF-kB and IRF4. Therefore, TLR7 and TLR9, like TLR4, induce both inflammatory and antiviral responses. Details of NF-kB activation are discussed in Chapter 7.
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