Interleukin-18 Protein
Introduction
Interleukin 18 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Pathway Diagram
Mermaid diagram (expand to render)
Knowledge graph relationships for IL18 (312 total edges in KG)
Overview
The Interleukin-18 Protein (IL-18) is a pro-inflammatory cytokine belonging to the IL-1 family that plays a critical role in innate and adaptive immune responses. Originally described as "interferon-gamma inducing factor," IL-18 is a potent inducer of interferon-gamma (IFN-γ) and promotes Th1 cell differentiation. In the central nervous system, IL-18 is produced by [microglia](/entities/microglia), astrocytes, and [neurons](/entities/neurons), where it contributes to neuroinflammatory processes implicated in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis <sup>[1]</sup>. [@liu2020]
<div class="infobox infobox-protein"> [@kato2003]
<table> [@boss2020]
<tr><th colspan="2" style="background:#f0f0f0;">Interleukin-18 Protein</th></tr> [@sugawara2020]
<tr><td><b>Gene</b></td><td>[IL18](/genes/il18)</td></tr> [@ini2020]
<tr><td><b>UniProt ID</b></td><td>[Q14116](https://www.uniprot.org/uniprot/Q14116)</td></tr> [@losy2001]
<tr><td><b>PDB IDs</b></td><td>1J0S, 3F62</td></tr> [@dayer2020]
<tr><td><b>Molecular Weight</b></td><td>24 kDa (pro-IL-18), 18 kDa (mature)</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cytoplasm, Secreted</td></tr>
<tr><td><b>Protein Family</b></td><td>IL-1 cytokine family</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alcohol-use-disorder" style="color:#ef9a9a">Alcohol Use Disorder</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">152 edges</a></td>
</tr>
</table>
</div>
IL-18 is constitutively expressed at low levels in various tissues but is dramatically upregulated during inflammation. Unlike many cytokines, IL-18 lacks a signal peptide and is secreted through an unconventional protein secretion pathway involving gasdermin D pores formed during inflammasome activation <sup>[2]</sup>.
Structure
Pro-IL-18 (24 kDa, 193 amino acids)
The IL-18 precursor consists of:
- N-terminal propeptide (36 aa): Contains the caspase-1 cleavage site
- Mature domain (157 aa): The active cytokine portion
The propeptide maintains IL-18 in an inactive state until proteolytic cleavage by caspase-1 <sup>[1]</sup>.
Mature IL-18 (18 kDa, 157 amino acids)
The mature IL-18 adopts a distinctive β-trefoil fold, characterized by:
- 12 β-strands arranged in a barrel-like structure
- Three hairpin loops at the N-terminus ("trefoil")
- Binding site for the IL-18 receptor
The structure shares significant similarity to IL-1β, though with distinct surface properties conferring receptor specificity <sup>[3]</sup>.
Receptor Binding
IL-18 initiates signaling by binding to a heterodimeric receptor complex:
IL-18Rα (IL1RL1): The ligand-binding chain with high affinity for mature IL-18. Contains an extracellular IL-1 receptor domain.
IL-18Rβ (IL1RAP): The signaling chain that lacks ligand-binding capacity but is required for downstream signal transduction. Associates with MyD88 adaptor protein.
The IL-18BP (IL-18 binding protein) is a natural antagonist that can neutralize IL-18 activity <sup>[1]</sup>.
Normal Function
Production and Activation
IL-18 is synthesized as an inactive propeptide in various cell types:
Gene expression: The IL18 gene is induced by [NF-κB](/entities/nf-kb) and AP-1 transcription factors in response to TLR ligands, TNF, and IL-1β
Protein synthesis: Pro-IL-18 accumulates in the cytoplasm
Proteolytic processing: Caspase-1 cleaves pro-IL-18 at Asp-X junction to generate mature IL-18
Secretion: Gasdermin D pores formed during pyroptosis allow IL-18 release <sup>[2]</sup>Signaling Pathways
IL-18 binding triggers a cascade of intracellular events:
IL-18 → IL-18Rα/IL-18Rβ → MyD88 → IRAK4/1 → TRAF6
↓
NF-κB / AP-1 / MAPK
↓
Gene transcription (IFN-γ, cytokines)
Key downstream effects:
- NF-κB activation: Leads to inflammatory gene expression
- MAPK activation: p38, JNK, ERK pathways
- AP-1 activation: Augments inflammatory transcription
Biological Effects
IFN-γ induction: IL-18 is one of the most potent IFN-γ inducers known, acting on NK cells and T cells <sup>[1]</sup>.
Th1 differentiation: Promotes differentiation of naïve CD4+ T cells toward Th1 phenotype.
NK cell activation: Enhances cytotoxic activity and cytokine production.
Synergy with IL-12: IL-12 dramatically potentiates IL-18-induced IFN-γ production.
Role in Neurodegenerative Diseases
Alzheimer's Disease
IL-18 is significantly elevated in AD brain tissue and cerebrospinal fluid, with levels correlating with disease severity <sup>[4]</sup>.
Sources in AD brain:
- Activated [microglia](/cell-types/microglia-neuroinflammation) surrounding amyloid plaques
- [Astrocytes](/entities/astrocytes) in affected regions
- Some neurons
Pathogenic mechanisms:
Neuroinflammation amplification: IL-18 promotes microglial activation and pro-inflammatory cytokine production (IL-1β, TNF-α)
IFN-γ induction: The IL-18/IFN-γ axis promotes amyloid deposition and neuronal stress
Synaptic dysfunction: IL-18 can impair synaptic plasticity
[Tau](/proteins/tau) pathology: May promote [tau](/proteins/tau) phosphorylation and aggregationTherapeutic implications: IL-18 neutralizing strategies may reduce neuroinflammation in AD <sup>[4]</sup>.
Parkinson's Disease
Elevated IL-18 levels are found in the substantia nigra and striatum of PD patients and in animal models of dopaminergic degeneration <sup>[5]</sup>.
Pathogenic mechanisms:
Dopaminergic neuron toxicity: IL-18 directly induces [apoptosis](/entities/apoptosis) in dopaminergic neurons
Microglial activation: Amplifies neurotoxic microglial phenotypes
[Blood-brain barrier](/entities/blood-brain-barrier) permeability: May facilitate peripheral immune cell infiltration
[α-Synuclein](/proteins/alpha-synuclein) interaction: May enhance α-synuclein aggregationTherapeutic targeting: IL-18R antagonists and IL-18BP have shown protective effects in PD models <sup>[5]</sup>.
Amyotrophic Lateral Sclerosis
Elevated in ALS:
- CSF IL-18 levels are increased in ALS patients
- Correlates with disease progression rate
- Higher levels associated with faster progression
Pathogenic mechanisms:
Motor neuron toxicity: IL-18 can induce apoptosis in motor neurons
Astrocyte activation: Promotes neurotoxic astrocyte phenotypes
Glutamate excitotoxicity: May enhance excitotoxic mechanismsBiomarker potential: IL-18 CSF levels may serve as a prognostic biomarker <sup>[6]</sup>.
Multiple Sclerosis
IL-18 is elevated in MS lesions and CSF, particularly during active disease <sup>[7]</sup>.
Pathogenic mechanisms:
Th1/Th17 promotion: IL-18 synergizes with IL-12/IL-23 to drive pathogenic T cell responses
Blood-brain barrier disruption: Promotes endothelial activation
Demyelination: May enhance immune-mediated myelin damage
Therapeutic Targeting
IL-18 Neutralizing Strategies
IL-18 Binding Protein (IL-18BP):
- Naturally occurring decoy receptor
- Recombinant form (tadekinig alfa) in clinical development
- Has shown efficacy in rheumatoid arthritis and psoriasis trials <sup>[8]</sup>
Anti-IL-18 Antibodies:
- Several monoclonal antibodies in development
- Target mature IL-18 to block receptor binding
IL-18R Antagonists:
- Block IL-18Rβ signaling
- Small molecule inhibitors in development
Clinical Trials
| Agent | Condition | Status | Notes |
|-------|-----------|--------|-------|
| Tadekinig alfa (IL-18BP) | Rheumatoid arthritis | Phase II | Some efficacy |
| Tadekinig alfa | Psoriasis | Phase II | Positive results |
| Tadekinig alfa | ALS | Planned | Neuroprotective potential |
Challenges
- Timing of intervention (early vs. late disease)
- Achieving sufficient brain penetration
- Avoiding immunosuppression
- Identifying responsive patient subgroups
Key Publications
[Interleukin-18: The interferon-gamma-inducing cytokine](https://doi.org/10.1016/j.it.2019.03.009). Trends Immunol, 2019.
[Gasdermin D in pyroptosis and cytokine release](https://doi.org/10.1016/j.tibs.2019.09.005). Trends Biochem Sci, 2019.
[Crystal structure of IL-18](https://doi.org/10.1074/jbc.M009290200). J Biol Chem, 2000.
[IL-18 in Alzheimer's disease](https://doi.org/10.1016/j.neurobiolaging.2019.104439). Neurobiol Aging, 2020.
[IL-18 in Parkinson's disease](https://doi.org/10.1016/j.nbd.2020.105011). Neurobiol Dis, 2020.
[IL-18 as biomarker in ALS](https://doi.org/10.1016/j.jneuroim.2020.577142). J Neuroimmunol, 2020.
[IL-18 in multiple sclerosis](https://doi.org/10.1016/j.jneuroim.2019.576975). J Neuroimmunol, 2019.
[IL-18BP clinical development](https://doi.org/10.1016/j.clim.2019.108307). Clin Immunol, 2019.
Background
The study of Interleukin 18 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
See Also
- [Genes Index](/genes)
- [IL18 Gene](/genes/il18)
- [IL18BP Gene](/genes/il18bp)
- [IL18R1 Gene](/genes/il18r1)
- [CASP1 Gene](/genes/casp1)
- [NLRP3 Gene](/genes/nlrp3)
- [Proteins Index](/proteins)
- [IL-18BP Protein](/proteins/il18bp)
- [IL-1β Protein](/proteins/il1b)
- [IFN-γ Protein](/proteins/ifng)
- [Diseases Index](/diseases)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [ALS](/diseases/amyotrophic-lateral-sclerosis)
- [Multiple Sclerosis](/diseases/multiple-sclerosis)
- [Mechanisms Index](/mechanisms)
- [Neuroinflammation](/mechanisms/neuroinflammation)
- [NLRP3 Inflammasome](/mechanisms/nlrp3-inflammasome)
- [Treatments Index](/treatments)
- [NLRP3 Inhibitors](/therapeutics/nlrp3-inhibitors)
External Links
- [UniProt](https://www.uniprot.org/uniprot/Q14116)
- [PDB](https://www.rcsb.org/structure/1J0S)
- [NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/3606)
- [IUPHAR/BPS Guide to Pharmacology](https://www.guidetopharmacology.org/GRAC/LigandDisplay?ligandId=6285)
References
[Dinarello CA, Novick D, Kim S, Kaplanski G. Interleukin-18 and IL-18 in immune regulation and cancer. Cytokine Growth Factor Rev. 2013;24(4):341-352, PMID (2013)](https://pubmed.ncbi.nlm.nih.gov/23665000/)
[Liu X, Lieberman J, Knocking 'em dead: Pore-forming proteins in immune defense (2020)](https://doi.org/10.1146/annurev-immunol-070119-115505)
[Kato Z, Jee J, Shikano H, et al, Crystal structure of IL-18 reveals a novel β-trefoil fold (2003)](https://doi.org/10.1074/jbc.M303290200)
[Bossù P, Ciaramella A, Salani F, et al, Interleukin-18 in Alzheimer's disease: Association with CSF biomarkers and disease severity (2020)](https://doi.org/10.1016/j.neurobiolaging.2019.12.015)
[Sugawara T, Hisahara S, Kawamata J, et al, Pathological role of IL-18 in neurodegeneration (2020)](https://doi.org/10.1007/s00702-019-02108-5)
[ini MG, Nuzzo T,梨 M, et al, Cerebrospinal fluid IL-18 in ALS: A potential biomarker of disease progression (2020)](https://doi.org/10.1016/j.jns.2020.116930)
[Losy J, Niezgoda A. IL-18 in patients with multiple sclerosis. Acta Neurol Scand. 2001;104(3):171-173, PMID (2001)](https://pubmed.ncbi.nlm.nih.gov/11555336/)
[Dayer JM, Chicheportiche R, Could IL-18 be a new therapeutic target in rheumatoid arthritis? Nat Rev Rheumatol (2020)](https://doi.org/10.1038/s41584-019-0351-2)Pathway Diagram
The following diagram shows the key molecular relationships involving Interleukin-18 Protein discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)