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Modulation of Toll–interleukin 1 receptor mediated signaling

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Abstract

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

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Abbreviations

DD :

Death domain

dsRNA :

Double-stranded RNA

IKK :

Inhibitory protein κB kinase

IL :

Interleukin

IL-1R :

Interleukin 1 receptor

IRAK :

Interleukin 1 receptor associated kinase

IRF :

Interferon regulatory factor

IκB :

Inhibitory protein κB

LPS :

Lipopolysaccharide

Mal :

MyD88-adaptor-like

MEKK:

Mitogen-activated extracellular signal regulated kinase activating kinase

MyD :

Myeloid differentiation factor

MyD88s :

Splicing variant of MyD88

NF :

Nuclear factor

NK :

Natural killer

RIP :

Receptor interacting protein

SIGIRR :

Single immunoglobulin interleukin 1 receptor related molecule

SOCS :

Suppressor of cytokine signaling

TAB :

Transforming growth factor β activated protein kinase 1 binding protein

TAK :

Transforming growth factor β activated kinase

TIR :

Toll-interleukin 1 receptor

TIRAP :

TIR domain containing adaptor protein

TLR :

Toll-like receptor

TRAF :

Tumor necrosis factor receptor associated factor

TRIF :

TIR domain containing adaptor inducing interferon β

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  1. Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA

    Xiaoxia Li & Jinzhong Qin

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Li, X., Qin, J. Modulation of Toll–interleukin 1 receptor mediated signaling. J Mol Med 83, 258–266 (2005). https://doi.org/10.1007/s00109-004-0622-4

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