Journal of Molecular Medicine

, Volume 83, Issue 4, pp 258–266 | Cite as

Modulation of Toll–interleukin 1 receptor mediated signaling

  • Xiaoxia LiEmail author
  • Jinzhong Qin


Toll-like receptors (TLRs) belong to the Toll–interleukin 1 receptor superfamily, which is defined by a common intracellular Toll-IL-1 receptor (TIR) domain. A group of TIR domain containing adaptors (MyD88, TIRAP, TRIF and TRAM), are differentially recruited to the Toll-IL-1 receptors, contributing to the specificity of signaling. The IL-1 mediated signaling pathway serves as a “prototype” for other family members. Genetic and biochemical studies reveal that IL-1R uses adaptor molecule MyD88 to mediate a very complex pathway, involving a cascade of kinases organized by multiple adapter molecules into signaling complexes, leading to activation of the transcription factor NFκB. Several Toll-like receptors utilize variations of the “prototype” pathway by employing different adaptor molecules. Double-stranded RNA triggered, TLR3-mediated signaling is independent of MyD88, IRAK4, and IRAK. The adapter molecule TRIF is utilized by TLR3 to mediate the activation of NFκB and IRF3. LPS-induced, TLR4-mediated signaling employs multiple TIR-domain containing adaptors, MyD88/TIRAP to mediate NFκB activation, TRIF/TRAM for IRF3 activation. Recent studies have also begun to unravel how these pathways are negatively regulated. SIGIRR (also known as TIR8), a member of TIR superfamily that does not activate the transcription factors NFκB and IRF3, instead negatively modulates responses. Cells from SIGIRR-null mice show enhanced activation in response to either IL-1 or certain Toll ligands. In addition to SIGIRR, several other negative regulators have been shown to inhibit the TIR signaling, including ST2, IRAKM, MyD88s, SOCS1, and Triad3A. The coordinated positive and negative regulation of the TIR signaling ensures the appropriate modulation of the innate and inflammatory responses


Interleukin 1 mediated signaling pathway Intracellular adaptor molecules TIR domain containing adaptors Toll–interleukin 1 receptor Toll-like receptors 



Death domain


Double-stranded RNA


Inhibitory protein κB kinase




Interleukin 1 receptor


Interleukin 1 receptor associated kinase


Interferon regulatory factor


Inhibitory protein κB






Mitogen-activated extracellular signal regulated kinase activating kinase


Myeloid differentiation factor


Splicing variant of MyD88


Nuclear factor


Natural killer


Receptor interacting protein


Single immunoglobulin interleukin 1 receptor related molecule


Suppressor of cytokine signaling


Transforming growth factor β activated protein kinase 1 binding protein


Transforming growth factor β activated kinase


Toll-interleukin 1 receptor


TIR domain containing adaptor protein


Toll-like receptor


Tumor necrosis factor receptor associated factor


TIR domain containing adaptor inducing interferon β


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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.Department of Immunology, Lerner Research InstituteCleveland Clinic FoundationClevelandUSA

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