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. 2014 Mar 3;5:79. doi: 10.3389/fimmu.2014.00079

Figure 2.

Figure 2

TLR-signaling pathways. TLR-4, TLR-5, and the heterodimers TLR-1/TLR-2 and TLR-2/TLR-6 are located on the cell surface where they are activated by the appropriate ligand. Conversely, TLR-3, TLR-7, TLR-8, and TLR-9 are located within endosomal compartments of the cell and recognize microbial and viral nucleic acids. Stimulation of TLR-1/TLR-2, TLR-2/TLR-6, TLR-4, and TLR-5 leads to the engagement of myeloid differentiation primary response protein (MyD88) and MYD88-adapter-like protein (MAL) with the TIR domain-containing adapter proteins. This stimulates downstream signaling pathways that involve the interactions between IL-1R-associated kinases (IRAKs) and the adapter molecules TNF receptor-associated factors (TRAFs) and activates mitogen-activated protein kinases (MAPKs) JUN N-terminal kinases (JNK) and p38. Activation of these kinases leads to the activation of transcriptional factors such as nuclear factor-κB (NF-κB), cyclic AMP-responsive element binding protein (CREB), and activator protein-1 (AP1). A major consequence of activation of surface TLRs is the induction of pro-inflammatory cytokines. Activation of TLR-7, TLR-8, and TLR-9 also leads to the engagement of MyD88, MAL, IRAKs, and IKKα, however, interferon-regulatory factors (IRFs) are activated, which leads to the production of type 1 interferons (IFN). Stimulation of TLR-3 results in the association of TIR domain-containing adapter protein inducing IFNβ (TRIF). This leads to the down stream signaling of TNF receptor-associated factors (TRAFs) and IKK leading to the activation of IRF3 and the production of type 1 IFNs. This image was adapted from Ref. (17).