# IL1R1 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- The *IL1R1* gene encodes the primary receptor for pro-inflammatory cytokines IL-1α and IL-1β, mediating innate immunity and inflammation through signaling cascades involving NF-κB and MAPK activation.
- *IL1R1* expression is tightly regulated by promoter elements, GC-rich 5' UTRs, alternative splicing generating soluble decoy receptors, and epigenetic modifications like DNA methylation and microRNA targeting.
- The IL1R1 protein features an extracellular domain with three immunoglobulin-like domains for ligand binding and an intracellular Toll/IL-1 receptor (TIR) domain essential for recruiting adaptor proteins like MyD88 to initiate downstream signaling.
- Genetic variants in *IL1R1*, particularly in non-coding regions, are associated with susceptibility to a broad spectrum of diseases including osteoarthritis, autoimmune disorders, various cancers, and neurological conditions like schizophrenia and depression.
- Therapeutic strategies targeting IL1R1 include FDA-approved biologics like Anakinra (IL-1Ra), Rilonacept (decoy receptor), and Canakinumab (anti-IL-1β), with ongoing research into small-molecule inhibitors and gene-editing approaches.
- The IL-1 system, mediated by IL1R1, plays a dual role in host-pathogen interactions, acting as a critical defense mechanism but also being a target for viral and bacterial immune evasion, with dysregulation contributing to immunopathology in infections like tuberculosis and sepsis.

---

## Executive Summary & Key Metadata

The Interleukin-1 Receptor Type 1 (IL1R1) gene encodes a critical transmembrane cytokine receptor that mediates the biological activities of interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β). As the primary signaling receptor for these potent pro-inflammatory cytokines, IL1R1 is a central node in innate immunity, inflammation, and the pathogenesis of numerous autoimmune, degenerative, and malignant diseases. The receptor's extracellular immunoglobulin-like domains bind IL-1 ligands, while its intracellular Toll/IL-1 receptor (TIR) domain initiates a conserved signaling cascade culminating in NF-κB and MAPK activation. Given its broad expression and central role in inflammation, IL1R1 has emerged as a major therapeutic target, with multiple biologics and small molecules in clinical development.

| Attribute | Detail |
| :--- | :--- |
| **HGNC Symbol** | IL1R1 |
| **UniProt Accession** | P14778 |
| **Representative PDB ID** | 1ITB (IL-1β/IL1R1 complex) |
| **Chromosomal Locus** | 2q11.2 |
| **Primary Molecular Function** | Interleukin-1 receptor activity; signal transduction; cytokine-mediated signaling pathway |
| **Disease & Pathology Associations** | Osteoarthritis, rheumatoid arthritis, asthma, cancer (pancreatic, breast, AML), IgG4-related disease, preeclampsia, tuberculosis, aortic dissection, depression, schizophrenia, traumatic brain injury |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Localization and Gene Context

The human *IL1R1* gene is located on the long arm of chromosome 2 at cytogenetic band 2q11.2. This region is part of a larger, evolutionarily conserved gene cluster encoding members of the interleukin-1 receptor family. The cluster spans approximately 500 kb and includes, in order from centromere to telomere, *IL1R2*, *IL1R1*, *IL1RL2* (IL-1Rrp2), *IL1RL1* (ST2), and *IL18R1* (IL-1Rrp) [1]. This genomic organization is highly conserved across mammals, suggesting shared regulatory elements and a common evolutionary ancestry through gene duplication events [1]. The proximity of these genes is clinically relevant, as linkage disequilibrium across the cluster can confound genetic association studies, making it difficult to attribute phenotypic effects to a single gene [2].

The reference genome assembly (GRCh38/hg38) places *IL1R1* between base pairs 102,100,000 and 102,200,000 on the forward strand. The gene spans approximately 40 kb of genomic DNA and contains 13 exons, with the translational start site located in exon 1 and the stop codon in exon 13. The 5' untranslated region (UTR) is encoded by a portion of exon 1 and is unusually long and GC-rich, a feature that contributes to the formation of stable secondary structures that regulate translation [3].

### 1.2 Promoter Architecture and Transcriptional Regulation

The *IL1R1* promoter lacks a canonical TATA box but contains multiple GC boxes, which serve as binding sites for the constitutively expressed transcription factor Sp1. This promoter architecture is characteristic of housekeeping genes, yet *IL1R1* expression is highly inducible and cell-type specific, indicating the presence of more complex regulatory logic. Several cis-acting elements have been identified within the proximal promoter region, including binding sites for NF-κB, C/EBPβ, and AP-1. These elements allow for rapid transcriptional upregulation in response to inflammatory stimuli, including IL-1 itself, TNF-α, and LPS, establishing a positive feedback loop that amplifies inflammatory signals.

The 5' UTR of *IL1R1* is a hotspot for genetic variation. Polymorphisms in this region have been shown to affect transcriptional activity and are linked to altered plasma levels of the soluble form of the receptor (sIL-1RI). Specifically, a study by Bergholdt et al. identified several novel single nucleotide polymorphisms (SNPs) in the 5' UTR that were in strong linkage disequilibrium with type 1 diabetes susceptibility, and these variants correlated with changes in circulating IL-1RI levels [3]. This suggests that regulatory polymorphisms in the 5' UTR can functionally impact the receptor's expression and contribute to disease risk.

### 1.3 Alternative Splicing and Isoforms

Alternative splicing of the *IL1R1* primary transcript generates multiple mRNA isoforms, although the functional significance of many of these remains under investigation. The predominant, fully functional isoform encodes the membrane-bound receptor. A second major isoform results from the use of an alternative polyadenylation signal, producing a transcript that encodes a soluble form of the receptor (sIL-1RI). This soluble receptor lacks the transmembrane and cytoplasmic domains and is secreted from cells, where it acts as a decoy receptor, binding IL-1 ligands and preventing them from interacting with membrane-bound receptors. The balance between the membrane-bound and soluble isoforms is a critical regulatory checkpoint in the IL-1 system.

Additional splice variants have been described that lack specific exons, potentially altering ligand-binding affinity or intracellular signaling capacity. For example, a variant lacking exon 2 has been reported, which would disrupt the first immunoglobulin-like domain and likely abrogate ligand binding. The expression of these minor isoforms is often tissue-specific and may be dysregulated in disease states, although their precise roles require further elucidation.

### 1.4 Epigenetic Regulation

DNA methylation at CpG sites within the *IL1R1* promoter and gene body is a key mechanism controlling its expression. A study by Roshanzamir and Hassan-Zadeh demonstrated that hyperglycemia in type 2 diabetic patients is associated with altered methylation of specific CpG sites in both the *IL1B* and *IL1R1* genes [4]. These methylation changes correlated with changes in gene expression, suggesting that metabolic stress can induce long-lasting epigenetic modifications that affect the IL-1 signaling axis. Furthermore, the microRNA miR-197-3p has been shown to directly target the *IL1R1* 3' UTR, downregulating its expression and modulating inflammation in the context of Familial Mediterranean Fever [5]. This adds a layer of post-transcriptional regulation to the control of IL1R1 levels.

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Primary Structure and Domain Organization

The IL1R1 protein is a type I transmembrane glycoprotein with a mature length of 569 amino acids after cleavage of a 17-amino-acid signal peptide. The protein is organized into three principal domains: a large extracellular domain (ECD), a single-pass transmembrane helix, and an intracellular domain. The ECD is responsible for ligand binding and is composed of three immunoglobulin (Ig)-like domains. These domains are arranged in a tandem, linear fashion, creating a long, extended structure that protrudes from the cell surface.

The three Ig-like domains are designated D1, D2, and D3, starting from the N-terminus. Each domain adopts a classic immunoglobulin fold, consisting of a sandwich of two β-sheets. The ligand-binding site is formed primarily by the interface between D1 and D2, with D3 contributing to the stability of the complex. The transmembrane domain is a single hydrophobic α-helix that anchors the receptor in the plasma membrane. The intracellular domain, which is essential for signal transduction, contains the Toll/Interleukin-1 Receptor (TIR) domain. This domain is structurally conserved across the IL-1 receptor family and the Toll-like receptor (TLR) family, highlighting the shared evolutionary origin of these innate immune pathways.

### 2.2 The Ligand-Binding Interface

High-resolution crystal structures of IL1R1 in complex with IL-1β (PDB: 1ITB) and IL-1α have provided atomic-level details of the interaction. The binding interface is extensive, burying a surface area of approximately 2,000 Ų. The primary binding site is located in the groove between the D1 and D2 domains of the receptor. Key residues in this groove form hydrogen bonds and hydrophobic contacts with residues on the surface of the IL-1 ligand. The interaction is characterized by a high degree of shape complementarity, with the receptor's binding pocket wrapping around a protruding loop of the cytokine.

The binding of IL-1 to IL1R1 is the first step in the formation of a high-affinity signaling complex. The initial IL-1/IL1R1 binary complex has a relatively low affinity (Kd ~ 1-5 nM). However, this complex then recruits a second receptor subunit, the IL-1 receptor accessory protein (IL1RAP), to form a high-affinity ternary complex. The recruitment of IL1RAP is mediated by interactions between the D3 domain of IL1R1 and the D3 domain of IL1RAP, as well as contacts with the bound IL-1 ligand. The formation of this ternary complex brings the TIR domains of IL1R1 and IL1RAP into close proximity, which is the critical event that initiates intracellular signaling.

### 2.3 The Intracellular TIR Domain

The TIR domain is a globular domain of approximately 140 amino acids, composed of a central five-stranded parallel β-sheet surrounded by five α-helices. The domain is named for its presence in Toll-like receptors and IL-1 receptors. The TIR domain of IL1R1 contains three highly conserved sequence motifs, known as Box 1, Box 2, and Box 3. These boxes are critical for the recruitment of downstream signaling molecules. Box 1 and Box 2 are involved in the interaction with the TIR domain of IL1RAP, while Box 3 is essential for the recruitment of the adaptor protein MyD88. Mutations in these boxes, particularly in Box 2, abolish signaling, confirming their functional importance.

The TIR domain does not possess intrinsic enzymatic activity. Instead, it functions as a protein-protein interaction module, nucleating the assembly of a large signaling complex. Upon ligand-induced dimerization with IL1RAP, the TIR domains of the two receptors form a platform for the recruitment of the cytosolic adaptor protein MyD88. This interaction is mediated by homotypic TIR-TIR domain interactions between the receptor and the adaptor.

> **[Interactive 3D Protein Visualizer: Load IL1R1 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=P14778)**
>
> Use the interactive viewer to explore the three-dimensional structure of the IL1R1 protein. The tool allows you to rotate the molecule, zoom into specific domains, and visualize the amino acid side chains. You can load the structure of the IL-1β/IL1R1 complex (PDB: 1ITB) to see the ligand-binding interface in detail, or view the isolated receptor to study its domain architecture. This tool is essential for understanding the structural basis of IL1R1 function and for visualizing the location of pathogenic mutations.

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 The Canonical IL-1 Signaling Cascade

The primary function of IL1R1 is to transduce the signal from its ligands, IL-1α and IL-1β, across the plasma membrane. The signaling cascade is initiated by the formation of the ternary complex (IL-1/IL1R1/IL1RAP), which triggers the recruitment of the adaptor protein MyD88 to the TIR domain of IL1R1. MyD88 is a bipartite adaptor protein with an N-terminal death domain (DD) and a C-terminal TIR domain. The TIR domain of MyD88 interacts with the TIR domain of IL1R1, while its death domain recruits members of the IRAK (IL-1 receptor-associated kinase) family.

The first kinase recruited is IRAK4, which binds to MyD88 via death domain interactions. IRAK4 then phosphorylates and activates IRAK1 and IRAK2. These activated IRAKs dissociate from the receptor complex and interact with the E3 ubiquitin ligase TRAF6 (TNF receptor-associated factor 6). TRAF6, in conjunction with the ubiquitin-conjugating enzyme UBC13 and the E2 variant UEV1A, catalyzes the synthesis of K63-linked polyubiquitin chains on target proteins, including TRAF6 itself and the adaptor protein TAB2/3.

The K63-linked polyubiquitin chains serve as a scaffold for the recruitment of the TAK1 (TGF-β-activated kinase 1) complex, which is composed of TAK1, TAB1, TAB2, and TAB3. TAK1 is activated upon binding to the ubiquitin chains and subsequently phosphorylates two key downstream pathways: the IKK complex and the MAPK pathways. The IKK complex, consisting of IKKα, IKKβ, and NEMO (IKKγ), phosphorylates the inhibitor of NF-κB (IκBα), targeting it for K48-linked polyubiquitination and proteasomal degradation. This releases NF-κB (typically the p50/p65 heterodimer) to translocate to the nucleus and drive the transcription of a vast array of pro-inflammatory genes, including cytokines, chemokines, adhesion molecules, and anti-apoptotic factors.

Simultaneously, TAK1 activates the mitogen-activated protein kinase (MAPK) cascades, including the ERK, JNK, and p38 pathways. These pathways lead to the activation of transcription factors such as AP-1 (c-Fos/c-Jun) and ATF-2, which cooperate with NF-κB to orchestrate the full inflammatory gene expression program.

```mermaid
sequenceDiagram
    participant L as "IL-1β"
    participant R as "IL1R1"
    participant A as "IL1RAP"
    participant M as "MyD88"
    participant K4 as "IRAK4"
    participant K1 as "IRAK1/2"
    participant T6 as "TRAF6"
    participant T1 as "TAK1"
    participant IKK as "IKK Complex"
    participant NF as "NF-κB"
    participant Nuc as "Nucleus"
    L->>R: Binds
    R->>A: Recruits IL1RAP
    A->>M: Recruits MyD88
    M->>K4: Recruits & Activates
    K4->>K1: Phosphorylates
    K1->>T6: Recruits & Activates
    T6->>T1: Ubiquitinates & Activates
    T1->>IKK: Phosphorylates
    IKK->>NF: Phosphorylates IκBα (Degradation)
    NF->>Nuc: Translocates
    Nuc->>Nuc: Transcribes Pro-inflammatory Genes
```

### 3.2 Regulation and Feedback Mechanisms

The IL-1 signaling pathway is subject to multiple layers of negative regulation to prevent excessive inflammation. One of the most important is the production of the IL-1 receptor antagonist (IL-1Ra). IL-1Ra binds to IL1R1 with an affinity similar to that of IL-1β but does not recruit IL1RAP, thereby acting as a competitive antagonist. The balance between IL-1 and IL-1Ra is a critical determinant of the net inflammatory tone.

Another key regulatory mechanism is the expression of the decoy receptor IL1R2. This receptor has an extracellular domain that binds IL-1 but lacks a functional intracellular TIR domain, so it cannot signal. IL1R2 acts as a "molecular trap," sequestering IL-1 and preventing its interaction with IL1R1. The soluble form of IL1R1 (sIL-1RI) also functions as a decoy, and its levels are regulated by proteolytic cleavage (shedding) of the membrane-bound receptor.

Intracellularly, the pathway is regulated by several proteins, including the suppressor of cytokine signaling (SOCS) proteins and the A20 deubiquitinase. SOCS1 has been shown to inhibit IL-1 signaling by binding to IRAK1 and promoting its degradation. A20 removes the K63-linked ubiquitin chains from TRAF6, thereby terminating the signal. Additionally, microRNAs such as miR-21 and miR-495 have been shown to directly target *IL1R1* mRNA, providing another layer of post-transcriptional control [6, 7].

### 3.3 Non-Canonical and Cell-Type-Specific Functions

While the MyD88-dependent pathway is the primary signaling mechanism, IL1R1 can also activate other pathways in a cell-type-specific manner. For example, in certain cell types, IL-1 signaling can activate the PI3K/Akt pathway, which promotes cell survival and proliferation. This pathway is particularly relevant in cancer, where IL-1 has been shown to promote tumor growth and metastasis [8].

The cellular response to IL-1 is highly context-dependent. In immune cells like macrophages, IL-1 is a potent activator of pro-inflammatory gene expression. In fibroblasts, it promotes proliferation and the production of extracellular matrix components, contributing to fibrosis [9, 10]. In endothelial cells, IL-1 increases the expression of adhesion molecules, promoting leukocyte extravasation. In neurons, IL-1 can modulate synaptic plasticity and neurogenesis, and its dysregulation is implicated in neuroinflammation and neurodegeneration [11, 12, 13]. The specific response is determined by the cell type, the local microenvironment, and the duration and intensity of the signal.

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Genetic Variants and Disease Susceptibility

The *IL1R1* gene is highly polymorphic, and numerous SNPs have been associated with susceptibility to a wide range of inflammatory and autoimmune diseases. These variants are often located in non-coding regions, such as the promoter, 5' UTR, or introns, and are thought to affect gene expression levels rather than the protein structure.

- **Osteoarthritis (OA):** Multiple studies have linked *IL1R1* polymorphisms to OA risk. A study in the Chinese Han population found that SNPs in *IL1R1* were significantly associated with knee OA risk [1]. Another study identified allelic variants of *IL1R1* that associate with severe hand OA [2]. The IL1R1-IL1A-IL1B-IL1RN gene cluster has been a major focus of OA genetics, with extended haplotypes showing strong association with the disease [2].
- **IgG4-Related Disease (IgG4-RD):** A study by Umemura et al. found that *IL1R1* gene variants associate with disease susceptibility to IgG4-related periaortitis/periarteritis, a cardiovascular manifestation of IgG4-RD [3].
- **Preeclampsia:** The SNP rs2071374 in *IL1R1* has been associated with the risk of preeclampsia, a pregnancy-specific hypertensive disorder [4].
- **Asthma:** Polymorphisms in *IL1R1* have been associated with childhood asthma [5]. A study on airway gene expression found that IL-1 pathway mediators, including IL1R1, predict exacerbation risk in obstructive airway disease [6].
- **Ankylosing Spondylitis (AS):** *IL1R1* polymorphisms have been found to be associated with AS in the Han Chinese population [7].
- **Tuberculosis (TB):** A pilot study found that *IL1R1* and *IL1R2* polymorphisms were associated with TB risk [8].
- **Cancer:** *IL1R1* variants have been linked to susceptibility to various cancers, including thyroid cancer [9], head and neck cancer [10], and breast cancer [11]. High *IL1R1* expression has been shown to predict poor survival in acute myeloid leukemia (AML) [12] and pancreatic adenocarcinoma [13].
- **Other Diseases:** *IL1R1* variants have also been implicated in osteonecrosis of the femoral head [1], aggressive periodontitis [2], celiac disease [3], and aortic dissection [4].

### 4.2 Coding Variants and Structural Impact

While most disease-associated variants are non-coding, some coding variants have been identified. A study by Jiang et al. identified an *IL1R1* coding variant that was associated with plasma-level soluble ST2 and the risk of aortic dissection [4]. This suggests that changes in the IL1R1 protein sequence can have functional consequences that extend beyond the receptor itself, potentially affecting the balance of related signaling pathways.

The functional impact of coding variants is often predicted using *in silico* tools such as SIFT and PolyPhen. However, the clinical significance of many of these variants remains uncertain, and functional assays are needed to confirm their effects on protein expression, ligand binding, and signaling. The ClinVar database classifies many *IL1R1* variants as "benign" or "likely benign," but a significant number are of "uncertain significance," highlighting the need for further research.

### 4.3 IL1R1 in Neuroinflammation and Psychiatric Disorders

The role of IL1R1 in the central nervous system (CNS) is an area of intense investigation. IL-1 signaling in the brain is a key mediator of neuroinflammation, which is a feature of many neurological and psychiatric disorders.

- **Schizophrenia:** A subgroup of schizophrenia patients exhibits elevated inflammation in the brain. Studies have shown that NF-κB pathway gene expression, including IL1R1, is elevated in the midbrain of these patients [12]. Furthermore, a schizophrenia subgroup with elevated inflammation displays altered microglia and neurogenesis marker gene expression in the subependymal zone [5, 13].
- **Depression:** IL1R1 has been identified as a potential diagnostic biomarker for depression, with its expression linked to lipid metabolism disorders [6]. It has also been identified as a novel biomarker linking depressive disorder and Alzheimer's disease [7].
- **Traumatic Brain Injury (TBI):** IL1R1 is a critical regulator of TBI-associated neuroinflammation. Inhibitors of IL1R1 and CSF1R have been shown to synergistically attenuate the early pathogenesis of TBI in mice [8].
- **Chronic Pain:** IL1R1 is a chronic pain-related gene. Its expression profiling has been studied to understand its clinical significance in pain management [9]. A novel subset of polymodal nociceptors expressing IL1R1 has been identified, and deletion of *Il1r1* in TRPV1+ neurons prevented pain in mouse models [10].
- **Bell's Palsy:** Studies have suggested that IL1R1 may be associated with Bell's palsy, a form of facial nerve paralysis [11, 12].

### 4.4 IL1R1 in Metabolic and Cardiovascular Disease

IL1R1 signaling is also implicated in metabolic and cardiovascular diseases. In obesity, visceral adipose NLRP3 impairs cognition via IL1R1 on Cx3cr1+ cells [11]. IL1R1 mediates celastrol's leptin-sensitization and anti-obesity effects [13]. In the cardiovascular system, IL1R1 is involved in pulmonary hypertension [1] and myocardial ischemia-reperfusion injury [2]. The crosstalk between liver sinusoidal endothelial cells and hepatocytes via the IL-1α–IL1R1 axis exacerbates ischaemia/reperfusion injury in aged livers [3].

## 5. Host-Pathogen & Viral Interactions

The IL-1 system is a critical component of the host defense against pathogens, but it is also a target for immune evasion by pathogens.

### 5.1 Viral Interactions

Several viruses have evolved mechanisms to subvert IL-1 signaling. For example, poxviruses encode soluble IL-1 receptor homologs that bind IL-1 and neutralize its activity. While this is not a direct interaction with the human IL1R1 protein, it highlights the importance of the IL-1 pathway in antiviral immunity.

In the context of human disease, the interaction between IL1R1 and viruses is often indirect. For example, a study found an association between the *IL1R1* rs2234650 polymorphism and acute lymphoblastic leukemia (ALL) patients infected with HHV-6A [4]. This suggests that genetic variation in IL1R1 may influence the host's response to viral infection and the subsequent risk of disease. Furthermore, HIV-1 reservoir size has been associated with plasma levels of IL1R1, suggesting a link between the IL-1 system and HIV persistence [5].

### 5.2 Bacterial Interactions

Bacterial pathogens can also manipulate the IL-1 system. *Mycobacterium tuberculosis*, the causative agent of tuberculosis, can modulate IL-1 signaling to promote its survival within macrophages. The association of *IL1R1* polymorphisms with TB risk suggests that the host's IL-1 response is a determinant of susceptibility [8]. *Leishmania* species, which cause leishmaniasis, also modulate cytokine signaling pathways in infected macrophages, potentially affecting IL1R1 expression [6].

### 5.3 The IL-1 System as a Double-Edged Sword

The IL-1 response is essential for clearing infections, but excessive or dysregulated IL-1 signaling can cause immunopathology. This is exemplified in chronic granulomatous disease (CGD), where defects in NADPH oxidase lead to excessive inflammation and granuloma formation. Single-cell and spatial transcriptomics have revealed the pathogenesis of CGD, with IL1R1 likely playing a role in the hyperinflammatory state [7]. Similarly, in sepsis, the systemic inflammatory response driven by IL-1 can cause tissue damage and organ failure.

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

Given its central role in inflammation, IL1R1 is a prime target for therapeutic intervention. The strategies to modulate IL1R1 signaling include biologics that neutralize the ligands or block the receptor, and small molecules that inhibit downstream signaling components.

### 6.1 FDA-Approved Biologics

- **Anakinra (Kineret):** This is a recombinant, non-glycosylated form of the human IL-1 receptor antagonist (IL-1Ra). It works by competitively binding to IL1R1, thereby blocking the actions of IL-1α and IL-1β. Anakinra is FDA-approved for the treatment of rheumatoid arthritis, neonatal-onset multisystem inflammatory disease (NOMID), and deficiency of IL-1 receptor antagonist (DIRA).
- **Rilonacept (Arcalyst):** This is a dimeric fusion protein consisting of the extracellular portions of IL1R1 and IL1RAP linked to the Fc portion of human IgG1. It acts as a soluble decoy receptor, trapping IL-1 and preventing it from binding to cell-surface receptors. Rilonacept is approved for the treatment of cryopyrin-associated periodic syndromes (CAPS).
- **Canakinumab (Ilaris):** This is a fully human monoclonal antibody that specifically neutralizes IL-1β. It does not bind to IL-1α or IL-1Ra. Canakinumab is approved for several autoinflammatory conditions, including CAPS, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD).

### 6.2 Investigational Therapies and Preclinical Targets

- **IL1R1-Specific Antibodies:** While anakinra and rilonacept block the receptor, they also affect IL-1α and IL-1β signaling. An antibody specifically targeting IL1R1 could provide more selective blockade. Preclinical studies have explored anti-IL1R1 antibodies for conditions like traumatic brain injury [8].
- **Small-Molecule Inhibitors:** The TIR domain of IL1R1 is a potential target for small-molecule inhibitors that could block the recruitment of MyD88. However, developing drugs that disrupt protein-protein interactions is challenging, and no such inhibitors have reached clinical trials.
- **Inhibitors of Downstream Kinases:** Inhibitors of IRAK4 and TAK1 are being developed as a way to block the IL-1 signaling pathway downstream of the receptor. These inhibitors are being investigated for the treatment of inflammatory diseases and certain cancers.
- **CRISPR-Based Epigenome Editing:** A novel therapeutic approach involves using CRISPR/dCas9 to epigenetically silence the *IL1R1* gene. This has been explored as a gene therapy strategy for degenerative disc disease, where reducing IL-1 signaling could prevent disc degeneration [8, 9].
- **Combination Therapies:** In pancreatic cancer, fibroblast-specific IL1R1-p38 MAPK signaling sustains stromal inflammation and contributes to therapeutic resistance [9]. Targeting IL1R1 in combination with other therapies is being explored as a strategy to overcome resistance [10, 11]. The NFAT pathway has also been identified as a mediator of pro-tumorigenic inflammation in cancer-associated fibroblasts, and IL1R1 is a key downstream effector [10].

### 6.3 Pharmacogenomics

The response to IL-1-targeted therapies can be influenced by genetic variation in *IL1R1* and related genes. For example, in acute myeloid leukemia, high *IL1R1* expression predicts poor survival but a benefit from stem cell transplant [12]. This suggests that *IL1R1* expression levels could be used as a biomarker to guide treatment decisions. Similarly, a nine-gene signature, which may include *IL1R1*, has been developed to predict the response to preoperative chemoradiotherapy in locally advanced rectal cancer [12]. As our understanding of the pharmacogenomics of IL-1 blockade grows, it is likely that these therapies will be used in a more personalized manner.

## 7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and resources for the *IL1R1* gene and protein.

| Database | Accession / ID | Description |
| :--- | :--- | :--- |
| **NCBI Gene** | 3554 | Gene-specific information, genomic context, and links to other databases. |
| **Ensembl** | ENSG00000115594 | Genome annotation, transcripts, and variation data. |
| **UniProtKB** | P14778 | Protein sequence, function, and post-translational modifications. |
| **RCSB PDB** | 1ITB, 3O4O, 4DEP | Experimentally determined 3D structures of IL1R1 and its complexes. |
| **OMIM** | 147810 | Mendelian inheritance and disease associations. |
| **HGNC** | IL1R1 | Gene symbol and nomenclature. |
| **ClinVar** | Various | Clinical significance of genetic variants. |
| **STRING** | 9606.ENSP00000260323 | Protein-protein interaction networks. |
| **BioGRID** | 108585 | Protein-protein and genetic interactions. |
| **Gene Ontology (GO)** | GO:0004908, GO:0007165, GO:0006954 | Molecular function, biological process, and cellular component. |
| **Reactome** | R-HSA-446652 | Signaling pathways involving IL1R1. |
| **KEGG** | hsa04620 | Toll-like receptor signaling pathway (includes IL-1 signaling). |

## Related Clinical & Scientific Guides

* [SYNGR1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/neuroscience-genetics/syngr1-gene-structure-function-pathway)
* [RGS12 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/neuroscience-genetics/rgs12-gene-structure-function-pathway)
* [CHRNB1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/neuroscience-genetics/chrnb1-gene-structure-function-pathway)

## References

[1] Zhou, L., Wu, C., Li, R., Wang, L., & Han, D. (2023). The expression profiling and clinical significance of a chronic pain-related gene IL1R1. *Cellular and Molecular Biology*. https://www.semanticscholar.org/paper/b4163b9a451dcc68cea120cfee753b4c9d0e9cc4

[2] Umemura, T., Fujinaga, Y., Ashihara, N., Ozawa, M., Kuraishi, Y., Watanabe, T., Hamano, H., Meguro, A., Kawa, S., & Ota, M. (2022). IL1R1 gene variants associate with disease susceptibility to IgG4-related periaortitis/periarteritis in IgG4-related disease. *Gene*. https://www.semanticscholar.org/paper/96ca7e459a85037ee829ce5b60a36243b70e89f1

[3] Akkaya-Ulum, Y. Z., Akbaba, T. H., Tavukçuoğlu, Z., Chae, J., Yılmaz, E., Ozen, S., & Balcı-Peynircioğlu, B. (2021). Familial Mediterranean fever-related miR-197-3p targets IL1R1 gene and modulates inflammation in monocytes and synovial fibroblasts. *Scientific Reports*. https://www.semanticscholar.org/paper/837c4767309483e027271e4e990fba8758dd3849

[4] Sivaraj, N., Rachel K, V., Suvvari, T., Prasad, S., Boppana, S., & Vegi, P. (2021). Association of IL1R1 gene (SNP rs2071374) with the risk of preeclampsia. *Journal of Reproductive Immunology*. https://www.semanticscholar.org/paper/c36c8a4e2314138e56c2784257bff5c1d0e63d08

[5] Na, Y., Bai, R., Zhao, Z., Wei, Y., Li, D., Wang, Y., Sun, C., Sun, L., Zhang, B., Jin, T., & Liu, W. (2016). IL1R1 gene polymorphisms are associated with knee osteoarthritis risk in the Chinese Han population. *OncoTarget*. https://www.semanticscholar.org/paper/04d77412c238a2d2f81005a4293efdc4fb03ddca

[6] IL1R1 Gene. (2020). *Definitions*. https://www.semanticscholar.org/paper/5973e16e25424b718144d3547331693c6d4dd741

[7] Liu, Y., Liu, S., Wu, H., & Zhang, X. (2016). [Association between IL1R1 gene polymorphisms and childhood asthma]. *Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics*. https://www.semanticscholar.org/paper/44fd29e6f9edafa712c9cffe04fba50bcf64efcb

[8] Peng, S., Li, K., Hu, B., Liu, P., & Yang, Y. (2025). Identification of IL1R1 as a potential key PANoptosis-related gene in myocardial ischemia-reperfusion injury using machine learning. *Scientific Reports*. https://www.semanticscholar.org/paper/c5f20008d2ad58ffc1d032e2e728a3c79e056c44

[9] Näkki, A., Kouhia, S., Saarela, J., Harilainen, A., Tallroth, K., Videman, T., Battié, M., Kaprio, J., Peltonen, L., & Kujala, U. (2010). Allelic variants of IL1R1 gene associate with severe hand osteoarthritis. *BMC Medical Genetics*. https://www.semanticscholar.org/paper/462c650918184fcbda165eea8c6f9544a851a4e5

[10] Bergholdt, R., Larsen, Z., Andersen, N., Johannesen, J., Kristiansen, O., Mandrup-Poulsen, T., Nerup, J., & Pociot, F. (2000). Characterization of new polymorphisms in the 5′UTR of the human interleukin-1 receptor type 1 (IL1R1) gene: linkage to type 1 diabetes and correlation to IL-1RI plasma level. *Genes and Immunity*. https://www.semanticscholar.org/paper/9f96fd1654359c0901e497843d99f1808e13c0f4

[11] Liu, Z., Li, X., Zhao, Y., Zhao, C., Chen, C., Li, Z., & Huo, W. (2022). Bell’s Palsy May Associate with Increased IL1R1: A Pilot Novel Gene and lncRNA Study. *Neurology and neurobiology*. https://www.semanticscholar.org/paper/20819ee3219c0794396c84a555a48724d598d34d

[12] Wang, S., Wang, Y., Strehle, J., Wernersbach, I., Papakonstantinou, E., Somnuke, P., Ritter, K., Klein, M., Tegeder, I., & Schäfer, M. K. E. (2025). CSF1R and IL1R1 inhibitors synergistically attenuate the early pathogenesis of traumatic brain injury in mice. *Neurotherapeutics*. https://www.semanticscholar.org/paper/550287588b5795207bf8efb8adc0de8db37af49b

[13] Liu, Y., Wang, T., Zhang, F., Liu, X., Hu, Z.,