GO:0042008 interleukin-18 receptor activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0042008 (interleukin-18 receptor activity) is a molecular function defined as combining with interleukin-18 and transmitting the signal across the membrane to initiate a change in cell activity.
• The receptor is a heterodimer of IL-18R1 (IL-1R5) and IL-18RAP (IL-1R7), sharing the IL-1 receptor family fold.
• IL-18 signaling drives NF-kB and MAPK activation, inducing IFN-gamma, and is central to inflammasome biology.
• IL-18BP acts as a secreted immune checkpoint that neutralizes IL-18 and limits receptor engagement, a major barrier to IL-18 immunotherapy.
• IL-18R1 expression on tumor and immune cells can promote immune evasion and tumor progression via NF-kB.
• CRISPR knockout, knock-in, and overexpression models are essential to dissect IL-18R1/IL-18RAP function in disease.
Description
Interleukin-18 receptor activity (GO:0042008) is the molecular function by which a cell binds interleukin-18 (IL-18) and transmits a signal across the plasma membrane to initiate a change in cell activity. IL-18 is a pro-inflammatory cytokine of the IL-1 family, first described as an interferon-gamma-inducing factor, and its receptor is a heterodimeric complex of IL-18R1 and IL-18RAP. This activity is a critical node linking innate inflammasome activation to adaptive immune responses, and it is implicated in autoimmunity, allergy, atherosclerosis, and cancer. Understanding GO:0042008 at the molecular, cellular, and organismal level is therefore essential for researchers studying inflammation, tumor immunology, and cytokine-directed therapeutics.
interleukin-18 receptor activity At A Glance
| GO ID | GO:0042008 |
|---|---|
| GO term | interleukin-18 receptor activity |
| Ontology | molecular_function |
| Synonym | IL-18R, IL-18 receptor activity |
| Major function | Binds interleukin-18 and transduces signals across the membrane to alter cell activity |
| Ligand | Interleukin-18 (IL-18), a pro-inflammatory cytokine of the IL-1 family |
| Receptor subunits | IL-18R1 (IL-1R5) and IL-18RAP (IL-1R7) heterodimer |
| Downstream pathways | NF-kB and MAPK signaling, leading to IFN-gamma production |
| Regulation | IL-18BP acts as a secreted decoy and immune checkpoint |
What Is GO:0042008?
According to the Gene Ontology, GO:0042008 (interleukin-18 receptor activity) is defined as combining with interleukin-18 and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity. In practical terms, this molecular function encompasses the ligand-binding and signal-transducing properties of the IL-18 receptor complex, which converts extracellular IL-18 binding into intracellular signaling events.
Why Is interleukin-18 receptor activity Important in Cell Biology?
GO:0042008 is important because IL-18 receptor activity is a central amplifier of inflammatory and immune responses, and its dysregulation contributes to a wide range of human diseases, including autoinflammatory conditions, allergy, atherosclerosis, and cancer. The receptor is also a therapeutic target: blocking IL-18BP to enhance IL-18 activity is being explored for cancer immunotherapy, while inhibiting IL-18 signaling may benefit autoimmune diseases. Thus, understanding the molecular details of this receptor activity is essential for both basic immunology and translational medicine.
• IL-18 receptor activity links inflammasome activation to IFN-gamma production and Th1 responses.
• It is required for NLRP3 inflammasome-dependent atherogenesis in mouse models.
• IL-18R1 expression modulates T cell responses in food allergy.
• IL-18BP is a secreted immune checkpoint that blocks IL-18 receptor engagement, limiting immunotherapy efficacy.
• ACSL6-activated IL-18R1-NF-kB signaling promotes tumor immune evasion and progression.
• IL-18 receptor signaling contributes to memory-like NK cell activation.
• The receptor is a potential target for cancer immunotherapy and anti-inflammatory drugs.
• Structural transitions in IL-18 maturation and signaling reveal therapeutic opportunities.
• IL-18 receptor activity is a biomarker and mechanistic node in inflammatory diseases.
• CRISPR models of IL-18R1 and IL-18RAP enable causal dissection of disease pathways.
Molecular Mechanism of interleukin-18 receptor activity
Ligand binding and receptor assembly
In simple terms: IL-18 binds to a two-part receptor on the cell surface, which then sends a signal inside.
Interleukin-18 receptor activity begins with the binding of IL-18 to the IL-18R1 subunit, which then recruits IL-18RAP to form a heterodimeric signaling complex. This assembly is analogous to other IL-1 receptor family members and is required for signal transduction. Structural studies have revealed that IL-18 undergoes conformational transitions that enable receptor engagement and signaling.
Signal transduction via TIR domains
In simple terms: Once the receptor is assembled, its intracellular tails recruit adaptor proteins that switch on inflammatory genes.
The intracellular TIR domains of IL-18R1 and IL-18RAP recruit the adaptor MyD88, leading to activation of IRAK kinases and downstream NF-kB and MAPK pathways. This signaling cascade induces expression of interferon-gamma and other pro-inflammatory genes. In tumor cells, ACSL6-activated IL-18R1-NF-kB signaling promotes immune evasion and tumor progression.
Regulation by IL-18BP
In simple terms: A decoy protein called IL-18BP mops up IL-18 and prevents it from activating the receptor.
IL-18 binding protein (IL-18BP) is a secreted decoy receptor that binds IL-18 with high affinity and prevents its interaction with the signaling receptor complex. IL-18BP acts as a soluble immune checkpoint and is a major barrier to IL-18 immunotherapy; engineered IL-18 variants that evade IL-18BP are being developed to enhance antitumor immunity.
Cell-type specific functions
In simple terms: Different immune cells use the IL-18 receptor to trigger different responses.
In NK cells, IL-18 receptor signaling together with IL-12 and IL-15 induces memory-like properties and enhanced effector functions. In T cells, IL-18R1 modulates allergic responses in food allergy models. In macrophages and vascular cells, IL-18 receptor activity contributes to atherosclerosis and plaque instability.
Key Genes Involved in GO:0042008 interleukin-18 receptor activity
The following genes encode the receptor subunits, ligand, regulatory proteins, and downstream signaling components that define interleukin-18 receptor activity.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL18R1 | Ligand-binding subunit of the IL-18 receptor | Knockout and knock-in models to study IL-18 signaling in immunity and cancer |
| IL18RAP | Signal-transducing subunit of the IL-18 receptor | Essential for receptor assembly and downstream NF-kB activation |
| IL18 | Pro-inflammatory cytokine ligand for the receptor | Overexpression and point-mutation models to study IL-18 maturation and signaling |
| IL18BP | Secreted decoy receptor that neutralizes IL-18 | Knockout and overexpression models to enhance IL-18 immunotherapy |
| MYD88 | Adaptor protein recruited to the receptor TIR domains | Knockout models to dissect downstream signaling |
| IRAK1 | Kinase activated downstream of MyD88 | Point-mutation models to study kinase-dependent signaling |
| IRAK4 | Kinase that partners with IRAK1 | Knockout models to study innate immune signaling |
| TRAF6 | E3 ubiquitin ligase that activates NF-kB | Knockout models to study NF-kB activation |
| NFKB1 | Transcription factor downstream of IL-18R | Reporter and knockout models to measure pathway output |
| MAPK1 | Kinase in the MAPK pathway activated by IL-18R | Point-mutation models to study signaling specificity |
| MAPK3 | Kinase in the MAPK pathway activated by IL-18R | Point-mutation models to study signaling specificity |
| IFNG | Cytokine induced by IL-18 receptor signaling | Reporter models to measure functional output |
| NLRP3 | Inflammasome that activates IL-18 | Knockout models to study IL-18 maturation |
| CASP1 | Caspase that cleaves pro-IL-18 | Knockout models to study IL-18 processing |
| ACSL6 | Enzyme that activates IL-18R1-NF-kB signaling | Overexpression and knockout models in tumor immunology |
| GZMB | Effector molecule induced by IL-18 in NK cells | Reporter models to study NK cell activation |
| PRF1 | Effector molecule induced by IL-18 in NK cells | Reporter models to study NK cell activation |
How Is interleukin-18 receptor activity Regulated?
Interleukin-18 receptor activity is regulated at multiple levels. Extracellularly, IL-18BP acts as a high-affinity decoy receptor that sequesters IL-18 and prevents receptor engagement, functioning as a soluble immune checkpoint. Membrane expression of IL-18R1 and IL-18RAP is modulated by cytokines such as IL-12 and IL-15, which enhance receptor responsiveness in NK and T cells. Intracellularly, signaling is controlled by negative regulators of the MyD88-IRAK-TRAF6 axis, and structural transitions in IL-18 itself can influence receptor binding and signaling efficiency. Additionally, ACSL6-mediated activation of IL-18R1-NF-kB signaling represents a cell-intrinsic regulatory mechanism in tumor cells.
interleukin-18 receptor activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL18R1 | Tumor immune evasion and progression | Knockout and overexpression in tumor cell lines |
| IL18R1 | Food allergy and T cell responses | Knockout mice and T cell-specific deletion |
| IL18BP | Cancer immunotherapy resistance | Knockout and overexpression in tumor models |
| NLRP3 | Atherosclerosis and inflammation | Knockout mice and inflammasome assays |
| IL18RAP | Inflammatory signaling and autoimmunity | Knockout and point-mutation models |
Cancer and tumor immune evasion
IL-18 receptor activity can promote tumor progression by driving NF-kB-dependent immune evasion. ACSL6-activated IL-18R1-NF-kB signaling in tumor cells enhances immune evasion and tumor growth, suggesting that targeting this axis may improve immunotherapy. Conversely, IL-18BP acts as a checkpoint that limits IL-18-mediated antitumor immunity, and engineered IL-18 variants that evade IL-18BP are being developed to boost cancer immunotherapy.
Allergy and inflammatory diseases
IL-18R1 modulates T cell responses in food allergy, and IL-18 receptor signaling contributes to allergic inflammation. In atherosclerosis, NLRP3 inflammasome-dependent IL-18 production and receptor activity promote plaque formation and instability. These findings position IL-18 receptor activity as a therapeutic target in allergic and cardiovascular diseases.
NK cell memory and immunotherapy
Cytokine activation of NK cells, including IL-18 receptor signaling, induces memory-like properties that enhance antitumor responses. This has led to clinical interest in cytokine-induced memory-like NK cells for cancer immunotherapy, where IL-18 receptor activity is a key driver of NK cell activation and persistence.
From interleukin-18 receptor activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does IL18R1 mediate tumor immune evasion? | IL18R1 knockout tumor cell lines and syngeneic mouse models |
| How does IL-18BP regulate IL-18 immunotherapy? | IL18BP knockout mice and engineered IL-18 variants |
| What is the role of IL-18R1 in food allergy? | T cell-specific IL18R1 knockout mice |
| How does IL-18RAP contribute to signaling? | IL18RAP point-mutation knock-in cell lines |
| Can IL-18 receptor activity be tracked in live cells? | Tagged knock-in of IL18R1 with fluorescent reporter |
| Does IL-18 drive memory-like NK cells? | Overexpression of IL-18R subunits in primary NK cells |
How to Study the interleukin-18 receptor activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screening | Gene requirement for IL-18 signaling | Identify novel regulators of IL-18R activity |
| RNA-seq | Transcriptional changes downstream of IL-18R | Measure IFNG and inflammatory gene expression |
| Proteomics | Protein abundance and modifications | Detect IL-18R1/IL-18RAP complex formation |
| Surface plasmon resonance | Binding affinity of IL-18 to receptor | Characterize IL-18BP competition |
| Flow cytometry | Cell surface expression of IL-18R subunits | Assess receptor levels in immune subsets |
| NK cell cytotoxicity assay | Functional NK cell activation | Study memory-like NK cells |
| T cell proliferation assay | T cell responses to IL-18 | Model food allergy |
| Inflammasome activation assay | IL-18 maturation and release | Study atherosclerosis |
CRISPR knockout screens
Genome-wide CRISPR knockout screens can identify genes required for IL-18 receptor activity and downstream signaling. For example, knocking out IL18R1 or IL18RAP abolishes IL-18-induced NF-kB activation, and screens can uncover novel regulators of this pathway.
Transcriptomic and proteomic profiling
RNA-seq and proteomics can measure changes in gene expression and protein abundance following IL-18 stimulation. These methods reveal downstream targets such as IFNG and GZMB, and can identify feedback regulators like IL-18BP.
Structural and biochemical assays
Surface plasmon resonance and crystallography can measure IL-18 binding to IL-18R1 and IL-18RAP, and structural transitions during signaling. These assays are critical for understanding the molecular basis of receptor activity and for designing therapeutic inhibitors.
Functional immune assays
NK cell cytotoxicity assays, T cell proliferation assays, and cytokine release assays measure the functional consequences of IL-18 receptor activity. These are used to study memory-like NK cells and allergic responses.
How CRISPR Can Be Used to Study GO:0042008 interleukin-18 receptor activity
Knockout
CRISPR knockout of IL18R1 or IL18RAP completely abolishes interleukin-18 receptor activity, providing a clean loss-of-function model to study downstream signaling and disease phenotypes. Knockout of IL18BP enhances IL-18 availability and is used to study immunotherapy resistance.
Point Mutation
Point mutations in the ligand-binding domain of IL18R1 or in the TIR domain of IL18RAP can dissect specific residues required for IL-18 binding versus signal transduction. Such models are valuable for understanding structural transitions and for designing receptor antagonists.
Knock-in
Knock-in of tagged IL18R1 (e.g., fluorescent or epitope tags) allows real-time tracking of receptor localization and trafficking in live cells. Knock-in of disease-associated variants can model human inflammatory diseases.
Overexpression
Overexpression of IL18R1 and IL18RAP in cell lines or primary immune cells enhances IL-18 responsiveness and can drive constitutive NF-kB activation, modeling tumor immune evasion and chronic inflammation.
How EDITGENE Supports interleukin-18 receptor activity Research
Researchers studying interleukin-18 receptor activity-related genes often need to determine whether a candidate gene is causally involved in IL-18 signaling, immune evasion, or inflammatory disease. EDITGENE provides end-to-end CRISPR services to generate precisely engineered cell models that answer these questions.
Contact EDITGENE today to design your custom CRISPR model for interleukin-18 receptor activity research.
Frequently Asked Questions About interleukin-18 receptor activity
What is interleukin-18 receptor activity?
Interleukin-18 receptor activity (GO:0042008) is the molecular function of binding interleukin-18 and transmitting a signal across the membrane to initiate a change in cell activity.
What genes are involved in interleukin-18 receptor activity?
The key genes are IL18R1 and IL18RAP, which form the receptor heterodimer, and IL18, the ligand. Regulatory genes include IL18BP, MYD88, IRAK1/4, and TRAF6.
What is the GO ID for interleukin-18 receptor activity?
The GO ID is GO:0042008, under the molecular_function ontology.
How does IL-18 receptor signaling work?
IL-18 binds IL-18R1, which recruits IL-18RAP, leading to MyD88-dependent activation of NF-kB and MAPK pathways and induction of IFN-gamma.
What diseases are associated with IL-18 receptor activity?
It is implicated in cancer immune evasion, food allergy, atherosclerosis, and inflammatory diseases.
What is the role of IL-18BP in IL-18 receptor activity?
IL-18BP is a secreted decoy receptor that binds IL-18 and prevents it from activating the signaling receptor, acting as an immune checkpoint.
How can I study interleukin-18 receptor activity using CRISPR?
CRISPR knockout of IL18R1 or IL18RAP abolishes receptor activity, while knock-in of tagged receptors allows tracking. Overexpression enhances signaling.
What are the downstream effects of IL-18 receptor activation?
Activation leads to NF-kB and MAPK signaling, production of IFN-gamma, and enhanced NK and T cell effector functions.
Is IL-18 receptor activity a therapeutic target?
Yes, blocking IL-18BP to enhance IL-18 antitumor activity and inhibiting IL-18 signaling in autoimmunity are active areas of research.
What cell types express the IL-18 receptor?
It is expressed on NK cells, T cells, macrophages, and some tumor cells, where it modulates immune responses.
Conclusion
Interleukin-18 receptor activity (GO:0042008) is a fundamental molecular function that bridges innate inflammasome activation and adaptive immunity. Its dysregulation contributes to cancer, allergy, and atherosclerosis, making it a high-value target for therapeutic intervention. CRISPR-based models are indispensable for dissecting the causal roles of IL18R1, IL18RAP, and associated genes in these diseases.
References
- 1. Dinarello CA. 1999. Interleukin-18.. Methods 19(1):121-32 PMID: 10525448
- 2. Zhou T et al.. 2020. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy.. Nature 583(7817):609-614 PMID: 32581358
- 3. Sergi B et al.. 2004. Interleukin 18 receptor.. J Biol Regul Homeost Agents 18(1):55-61 PMID: 15323361
- 4. Kim EG et al.. 2022. Interleukin-18 Receptor α Modulates the T Cell Response in Food Allergy.. Allergy Asthma Immunol Res 14(4):424-438 PMID: 35837825
- 5. Dong Y et al.. 2024. Structural transitions enable interleukin-18 maturation and signaling.. Immunity 57(7):1533-1548.e10 PMID: 38733997
- 6. Di Y et al.. 2024. ACSL6-activated IL-18R1-NF-κB promotes IL-18-mediated tumor immune evasion and tumor progression.. Sci Adv 10(38):eadp0719 PMID: 39292786
- 7. Duewell P et al.. 2010. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.. Nature 464(7293):1357-61 PMID: 20428172
- 8. Romee R et al.. 2012. Cytokine activation induces human memory-like NK cells.. Blood 120(24):4751-60 PMID: 22983442
