Toll/interleukin-1 receptor (TIR) domain-mediated cellular signaling pathways

Apoptosis. 2015 Feb;20(2):196-209. doi: 10.1007/s10495-014-1073-1.


Innate immunity, which is the first line of host defense against invading microbial pathogens in multicellular organisms, occurs through germline-encoded pattern-recognition receptors. The Toll-like receptor/Interleukin (IL)-1 receptor (TLR/IL-1R) superfamily comprises proteins that contain the phylogenetically conserved Toll/IL-1 receptor (TIR) domain, which is responsible for the propagation of downstream signaling through recruitment of TIR domain containing cytosolic adaptor proteins such as MyD88, TIRAP/MAL, TRIF, TRAM and SARM. These interactions activate transcription factors that regulate the expression of various proinflammatory cytokines (IL-1, IL-6, IL-8 and TNF-α) and chemokines. Activation of the TLR/IL-1R signaling pathway promotes the onset of inflammatory diseases, autoimmune diseases and cancer; therefore, this pathway can be used for the development of therapeutic strategies against these types of pathogenesis. In this review paper, we illustrate the role of the TIR-TIR domain interaction with the TLR/IL-1R signaling pathway in inflammation and apoptosis and recent therapeutic drugs targeted to inhibit the downstream signaling cascade for treatment of inflammatory diseases and cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Apoptosis*
  • Humans
  • Immunity, Innate
  • Models, Molecular
  • Protein Interaction Domains and Motifs
  • Receptors, Interleukin-1 / chemistry
  • Signal Transduction*
  • Toll-Like Receptors / chemistry


  • Adaptor Proteins, Signal Transducing
  • Receptors, Interleukin-1
  • Toll-Like Receptors