Toll-like receptor (TLR) signaling plays an essential role in the innate immune response. Activation of TLR signaling through recognition of pathogen-associated molecular patterns leads to the transcriptional activation of genes encoding for pro-inflammatory cytokines, chemokines and co-stimulatory molecules. These molecules subsequently control the activation of antigen-specific adaptive immune response. TLRs have been pursued as potential therapeutic targets for various inflammatory diseases and cancer.
Human TLRs were first identified as homologs to the toll receptor in Drosophila . To date, ten proteins have been identified that belong to the human TLR family . All TLRs are transmembrane proteins that consist of a leucine-rich repeat extracellular domain (for recognizing specific pathogens), a transmembrane region and a Toll-IL-1R domain (for initiating intracellular signaling events).
Variations in TLR ligands initiate specific immunological responses:
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TNF interacts with many pathway targets, including:
Activation of most TLRs upon ligand binding results the activation of NF-kB and MAPK pathways to elicit regulatory responses. The signaling events initiated by TLR activation are mediated by unique interaction between TIR domain–containing cytosolic adapters, including: myeloid differentiation primary-response protein-88 (MyD88), TIR domain–containing adapter protein (TIRAP), TIR domain–containing adapter–inducing IFNb (TRIF) and TRIF-related adapter molecule (TRAM) .
MyD88 serves as the central adapter protein associating with IRAK4, which recruits and phosphorylates IRAK1. Following interaction with TRAF6, the activated IRAK complex phosphorylates TAB1 and TAK1, which in turn activate the NF-κB and MAPK pathways  leading the expression of interleukins (IL-1B, IL-6, IL-8, and IL-12), macrophage inflammatory proteins, (MIP-1a and MIP1b), and cytokines (RANTES and TNFα) . TLR3 and TLR7/TLR8 can mediate the activation of IRF3 and IRF7.TLR3 functions through a MyD88-independent pathway by interacting with TRIF, which activates a complex of IKKe, TRAF3, and TBK1 that phosphorylates IRF3 and IRF7 . Activation of IRF3 results in the induction of genes that stimulate T cell immunogenic responses. IRF7 promotes an antiviral immune response by the induction of IFNα and IFNβ gene expression.
Thermo Scientific™ offers antibodies, ELISAs, Luminex® multiplex assays and growth factors for key targets in the TLR signaling pathway.
Featured below is immunohistochemical and flow cytometry data using Thermo Scientific™ products.
Flow cytometry analysis of U251 cells using a TLR4 polyclonal antibody (Product # PA5-26689) (right) compared to a negative control cell (left) at a dilution of 1:10-50, followed by a FITC-conjugated goat anti-rabbit antibody.
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