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Journal of Molecular Medicine

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

Modulation of Toll–interleukin 1 receptor mediated signaling

  • Xiaoxia Li
  • Jinzhong Qin
Review

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

Keywords

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

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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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

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

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