IL1R1

Official Full Name

interleukin 1 receptor type 1

Organism

Homo sapiens

GeneID

3554

Background

This gene encodes a cytokine receptor that belongs to the interleukin-1 receptor family. The encoded protein is a receptor for interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist. It is an important mediator involved in many cytokine-induced immune and inflammatory responses. This gene is located in a cluster of related cytokine receptor genes on chromosome 2q12. [provided by RefSeq, Dec 2013]

Synonyms

P80; IL1R; CRMO3; IL1RA; CD121A; D2S1473; IL-1RT1; IL-1R-alpha;

Bio Chemical Class

Cytokine receptor

Protein Sequence

MKVLLRLICFIALLISSLEADKCKEREEKIILVSSANEIDVRPCPLNPNEHKGTITWYKDDSKTPVSTEQASRIHQHKEKLWFVPAKVEDSGHYYCVVRNSSYCLRIKISAKFVENEPNLCYNAQAIFKQKLPVAGDGGLVCPYMEFFKNENNELPKLQWYKDCKPLLLDNIHFSGVKDRLIVMNVAEKHRGNYTCHASYTYLGKQYPITRVIEFITLEENKPTRPVIVSPANETMEVDLGSQIQLICNVTGQLSDIAYWKWNGSVIDEDDPVLGEDYYSVENPANKRRSTLITVLNISEIESRFYKHPFTCFAKNTHGIDAAYIQLIYPVTNFQKHMIGICVTLTVIIVCSVFIYKIFKIDIVLWYRDSCYDFLPIKASDGKTYDAYILYPKTVGEGSTSDCDIFVFKVLPEVLEKQCGYKLFIYGRDDYVGEDIVEVINENVKKSRRLIIILVRETSGFSWLGGSSEEQIAMYNALVQDGIKVVLLELEKIQDYEKMPESIKFIKQKHGAIRWSGDFTQGPQSAKTRFWKNVRYHMPVQRRSPSSKHQLLSPATKEKLQREAHVPLG

Open

Disease

Rheumatoid arthritis

Approved Drug

1 +

Clinical Trial Drug

Discontinued Drug

1 +

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Detailed Information

IL-1R1, a member of the Toll-like receptor (TIR) superfamily, is a critical mediator of IL-1 cytokine signaling, playing a vital role in inflammation. As a membrane-bound receptor, it binds IL-1 ligands and initiates downstream inflammatory responses. Structurally, the extracellular portion of IL-1R1 consists of three immunoglobulin-like (Ig-like) domains, which are responsible for the receptor's interaction with IL-1 ligands. The cytoplasmic domain, approximately 200 amino acids in length, shares homology with other TIR family members. This structural characteristic makes IL-1R1 the first identified TIR receptor.

The crystal structure of the IL-1R1 extracellular domain bound to IL-1 has been resolved to 2.5 Å resolution, providing key insights into receptor-ligand interactions. The first two Ig domains (D1 and D2) are held in a rigid configuration by an inter-domain disulfide bond, while the third Ig domain (D3) is more flexible and closely connected to D2. The receptor wraps around IL-1, interacting through two primary areas: a large groove between D1 and D2, and a smaller contact region on D3. This structure outlines the essential interaction points for IL-1 binding, although specific details about the interaction with IL-1 are still unresolved.

Figure 1 illustrates the binding interactions and signaling mechanisms of IL-1 receptor complexes, highlighting how agonist and antagonist ligands interact with IL-1R1, IL-1R2, and their soluble forms, influencing ligand sequestration and signaling activation or inhibition. Figure 1. The IL-1 receptor complexes. (Boraschi D, et al., 2013)

Antagonist Binding to IL-1R1

Unlike IL-1, the antagonist IL-1Ra binds to IL-1R1 differently, which results in a distinct conformational change in the receptor. The crystal structure of the IL-1R1–IL-1Ra complex reveals that IL-1Ra binds primarily to the large groove between D1 and D2, but does not interact with D3, unlike the binding of IL-1. Despite its different binding pattern, IL-1Ra maintains high-affinity interactions with IL-1R1, which are sufficient to effectively compete with the agonist ligands IL-1 and IL-1β. Notably, the binding of IL-1Ra results in a less pronounced conformational change in IL-1R1 compared to the IL-1–IL-1R1 complex, with the receptor's structure being more extended and open. This difference is important for understanding the mechanisms through which IL-1Ra prevents the activation of IL-1R1 by its agonist ligands.

Shedding of IL-1R1

In addition to its role in ligand binding, IL-1R1 can undergo metalloproteinase-dependent shedding of its extracellular domain, which generates a soluble form of the receptor (sIL-1R1). This soluble receptor can act as a decoy, capturing IL-1 and preventing its interaction with the membrane-bound IL-1R1. Interestingly, sIL-1R1 also binds IL-1Ra, potentially diminishing its inhibitory effects. This dual role of sIL-1R1 highlights the complex regulation of IL-1 signaling, where soluble receptors both modulate the availability of agonists and antagonists in the extracellular space.

The soluble form of IL-1R1 also undergoes further processing after shedding. The C-terminal fragment of the extracellular domain is subject to intramembrane proteolysis by γ-secretase, which releases an intracellular domain that can be ubiquitinated. This intracellular fragment may play a role in downstream signaling, adding another layer of complexity to IL-1R1 signaling.

IL-1R1 Ligand Affinity and Competition

IL-1R1 has a high affinity for both its agonist ligands, IL-1 and IL-1β, as well as the antagonist IL-1Ra. The binding affinities of IL-1R1 for these ligands range from 0.1 to 1.0 nM, indicating a robust interaction with both pro-inflammatory cytokines and their inhibitors. This affinity underscores the effectiveness of IL-1Ra in competing with IL-1 and IL-1β for receptor binding, which is critical for regulating inflammatory responses. The ability of IL-1Ra to effectively block IL-1 signaling further highlights its therapeutic potential in conditions involving excessive inflammation.

While the soluble form of IL-1R1 (sIL-1R1) serves as a decoy for IL-1, it is not without drawbacks. By binding IL-1Ra, sIL-1R1 reduces the availability of this important antagonist, which can potentially amplify inflammatory responses in certain contexts. This dual interaction with both IL-1 and IL-1Ra suggests that the regulation of IL-1R1 activity is highly complex and may involve fine-tuned mechanisms to maintain a balance between pro-inflammatory and anti-inflammatory signals.

IL-38 and Its Interaction with IL-1R1

A newer player in the IL-1 receptor family, IL-38 (previously known as IL-1HY2 or IL-1F10), has shown potential for binding to IL-1R1. IL-38 is a cytokine that, when immobilized on a surface, has been reported to interact with sIL-1R1, although the binding affinity is slightly weaker than that of IL-1 or IL-1Ra. One study found that the affinity of IL-38 for sIL-1R1 was 93 nM, which is approximately five times weaker than IL-1 (21 nM) and IL-1Ra (36 nM). However, the experimental setup used to assess this binding was not optimal, leading to concerns about the reliability of the data.

More recent studies have failed to show significant binding of IL-38 to immobilized sIL-1R1 using low-sensitivity binding systems. In contrast, binding to another receptor, IL-1R6-Fc was detected. These findings suggest that while IL-38 might interact with IL-1R1, its binding characteristics require further investigation. The lack of a proper control with IL-1 in these experiments makes it difficult to draw definitive conclusions regarding the relevance of IL-38's interaction with IL-1R1.

References:

Boraschi D, Tagliabue A. The interleukin-1 receptor family. Semin Immunol. 2013;25(6):394-407.
Ku JL, Hsu JR, et al. Interplay among IL1R1, gut microbiota, and bile acids in metabolic dysfunction-associated steatotic liver disease: a comprehensive review. J Gastroenterol Hepatol. 2025;40(1):33-40.

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