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The IL-1 receptor/toll-like receptor superfamily: crucial receptors for inflammation and host defense

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Abstract

The interleukin 1 toll-like receptor superfamily is an expanding family of receptors, functioning as a rapid defense response to infection and injury, and possibly having other roles in human disease.

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Defining the IL-1R/TLR superfamily

Figure 1 illustrates the members of the IL-1R/TLR superfamily identified to date and the consensus sequence for the TIR domain. The type II IL-1R and its vaccinia ortholog B15R are the only members to lack a TIR domain. The superfamily splits into two major subfamilies: those that have three immunoglobulin (Ig) domains extracellularly, and those that have leucine-rich repeats that are extracellular (e.g. TLRs 1–6), the plant members being cytosolic. The former subgroup includes IL-1RI itself

Signal transduction

The presence of a conserved domain in a family of receptors suggests common signaling pathways. This appears to be the case for the IL-1R/TLR superfamily, as tested so far with IL-1, IL-18 and LPS. Common pathways include activation of the transcription factor NF-κB, p38 mitogen-activated protein kinase (MAPK) and Jun N-terminal kinase (reviewed in Ref. 1). The proteins that are currently known to participate in these pathways are illustrated in Fig. 2. Mice deficient in MyD88, IL-1R-associated

IL-18R and T1/ST-2: opposite effects on Th-cell divergence

As mentioned above, a recent finding concerns the role of the IL-18R complex and the T1/ST-2 receptor in Th-cell function. IL-18 has emerged as a defining cytokine for activation of Th1 cells. IL-18R-deficient mice exhibit impaired natural killer cells, cytotoxic T cells and interferon γ production4. Remarkably, the T1/ST-2 receptor, which is highly similar in its amino acid sequence to both chains of the IL-18R, is expressed only on Th2 cells and has been demonstrated to direct Th2 function5.

TLRs: receptors for LPS and other microbial products

Another exciting development has been the report that TLR-4 is utilized by LPS (14, 15, 16), while TLR-2 is involved in responses to microbial products from Gram-positive bacteria, including peptidoglycan from Staphylococcus aureus and lipoproteins from Borrelia burgdorferi (the causative agent in Lyme disease)16, 17, 18. It had been known for some time that the LPS response requires LPS-binding protein and CD14, but the signaling receptor remained a mystery. The demonstration that TLR-4

Is there a therapeutic role for blocking TLR function?

There are two strategies for reducing signal transduction of TLRs with the specific goal of reducing the consequences of their biological effects: (1) the use of specific soluble TLR family members to bind and ‘neutralize’ the respective microbial or mammalian ligands or class of ligands; and (2) the development of small molecules to prevent the cytoplasmic domains of TLRs from recruiting intracellular signaling molecules. An example of the former would be soluble TLR-2 or TLR-4 for treating

Conclusions

The IL-1R/TLR superfamily has emerged as an expanding family of receptors that arose early in evolution and whose function is to respond rapidly to infection and injury. The role of IL-1R in multiple pathologies is well established and it will be of interest to determine whether TLRs have roles other than those involving the response to infection. The finding that TLR-4 is important for responses to LPS may allow for novel means to intervene therapeutically during sepsis. Whether the TLRs have

Acknowledgements

L.O.N. wishes to thank The Health Research Board (Ireland), Enterprise Ireland, The National Pharmaceutical Biotechnology Center and the European Union for financial support. The authors apologize for the fact that, owing to space constraints, not all work in this area could be cited.

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