Interleukin-18 Protein

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Interleukin-18 Protein

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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

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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 [1]. [@liu2020]

<div class="infobox infobox-protein"> [@kato2003]
<table> [@boss2020]
<tr><th colspan="2" style="background:#f0f0f0;">Interleukin-18 Protein</th></tr> [@sugawara2020]
<tr><td>Gene</td><td>[IL18](/genes/il18)</td></tr> [@ini2020]
<tr><td>UniProt ID</td><td>[Q14116](https://www.uniprot.org/uniprot/Q14116)</td></tr> [@losy2001]
<tr><td>PDB IDs</td><td>1J0S, 3F62</td></tr> [@dayer2020]
<tr><td>Molecular Weight</td><td>24 kDa (pro-IL-18), 18 kDa (mature)</td></tr>
<tr><td>Subcellular Localization</td><td>Cytoplasm, Secreted</td></tr>
<tr><td>Protein Family</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 [2].

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 [1].

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 [3].

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 [1].

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 [2]

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 [1].

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 [4].

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 aggregation

Therapeutic implications: IL-18 neutralizing strategies may reduce neuroinflammation in AD [4].

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 [5].

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 aggregation

Therapeutic targeting: IL-18R antagonists and IL-18BP have shown protective effects in PD models [5].

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 mechanisms

Biomarker potential: IL-18 CSF levels may serve as a prognostic biomarker [6].

Multiple Sclerosis

IL-18 is elevated in MS lesions and CSF, particularly during active disease [7].

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 [8]

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.

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)

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Related Entities

IL18

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slug	proteins-il18
kg_node_id	IL18
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-2913b724ef06
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-il18'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

65%

Debates

0

Incoming

13

Outgoing

25

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Interleukin-18 Protein

Interleukin-18 Protein

Introduction

Pathway Diagram

Interleukin-18 Protein

Introduction

Pathway Diagram

Overview

Structure

Pro-IL-18 (24 kDa, 193 amino acids)

Mature IL-18 (18 kDa, 157 amino acids)

Receptor Binding

Normal Function

Production and Activation

Signaling Pathways

Biological Effects

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Multiple Sclerosis

Therapeutic Targeting

IL-18 Neutralizing Strategies

Clinical Trials

Challenges

Key Publications

Background

See Also

External Links

References

Pathway Diagram

💬 Discussion