TLR Pathway

• Description
• Reviews
• Pathway Key
• Pathway Products
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Pathway Description:

Toll-like receptors (TLRs) recognize distinct pathogen-associated molecular patterns and play a critical role in innate immune responses. They participate in the first line of defense against invading pathogens and play a significant role in inflammation, immune cell regulation, survival and proliferation. To date 11 members of the TLR family have been identified, of which TLR1, 2, 4, 5 and 6 are located on the cell surface and TLR3, 7, 8 and 9 are localized to the endosomal/lysosomal compartment. The activation of the TLR signaling pathway originates from the cytoplasmic Toll/IL-1 receptor (TIR) domain that associates with a TIR domain-containing adaptor, MyD88. Upon stimulation with ligands, MyD88 recruits IL-1 receptor-associated kinase (IRAK) to TLRs through interaction of the death domains of both molecules. IRAK activated by phosphorylation then associates with TRAF6, finally leading to activation of JNK and NF-κB. Tollip and IRAK-M interact with IRAK-1 and negatively regulate the TLR-mediated signaling pathways. MyD88-independent pathways induce activation of IRF3 and expression of interferon-β. TIR-domain containing adaptors such as TIRAP, TRIF and TRAM regulate TLR-mediated signaling pathways by providing specificity for individual TLR signaling cascades.

Selected Reviews:

• Barrat FJ, Coffman RL (2008) Development of TLR inhibitors for the treatment of autoimmune diseases. Immunol. Rev. 223, 271–83.
• Miggin SM, O'Neill LA (2006) New insights into the regulation of TLR signaling. J. Leukoc. Biol. 80(2), 220–6.
• Pasare C, Medzhitov R (2005) Toll-like receptors: linking innate and adaptive immunity. Adv. Exp. Med. Biol. 560, 11–8.
• Moore CB, Ting JP (2008) Regulation of mitochondrial antiviral signaling pathways. Immunity 28(6), 735–9.
• Verstrepen L, Bekaert T, Chau TL, Tavernier J, Chariot A, Beyaert R (2008) TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme. Cell. Mol. Life Sci. [Epub ahead of print].
• Tamura T, Yanai H, Savitsky D, Taniguchi T (2008) The IRF family transcription factors in immunity and oncogenesis. Annu. Rev. Immunol. 26, 535–84.

CST would like to thank Dr. Pranoti Mandrekar, University of Massachusetts Medical School, Worcester, Massachusetts, for contributing to this TLR Pathway diagram.