IL18 Gene

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IL18 Gene (Interleukin-18)

Introduction

Il18 Gene 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

graph TD IL18["IL-18 Interleukin-18"] --> IL18R["IL-18 Receptor Complex"] IL18R --> MYD88["MyD88 Adaptor"] MYD88 --> NFkB["NF-kB Activation"] MYD88 --> MAPK["MAPK/JNK Signaling"] NFkB --> IFNG["IFN-gamma Production"] CASP1["Caspase-1 Inflammasome"] --> IL18 NLRP3["NLRP3 Inflammasome"] --> CASP1 IL18BP["IL-18BP Binding Protein"] -.->|"Inhibits"| IL18 IFNG --> MICROGLIA["Microglial M1 Activation"] MICROGLIA --> NEUROINFLAM["Neuroinflammation"] style IL18 fill:#5c1515,color:#e0e0e0,stroke:#c62828 style NFkB fill:#6d3000,color:#e0e0e0 style NLRP3 fill:#5d4400,color:#e0e0e0 style IL18BP fill:#1b5e20,color:#e0e0e0

Overview

The IL18 Gene encodes interleukin-18, a pro-inflammatory cytokine belonging to the IL-1 family. IL-18 plays a crucial role in innate immunity, inflammation, and has been strongly implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, ALS, and multiple sclerosis. Originally discovered as an interferon-gamma (IFN-γ) inducing factor, IL-18 is now recognized as a key mediator of neuroinflammation in the central nervous system. [@dinarello2013]

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IL18 Gene (Interleukin-18)

Introduction

Il18 Gene 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)

Overview

<div class="infobox infobox-gene"> [@hafizi2020]
<table> [@ojala2009]
<tr><th colspan="2" style="background:#f0f0f0;">IL18 - Interleukin-18</th></tr> [@sugama2020]
<tr><td>Full Name</td><td>Interleukin-18</td></tr> [@debyser2021]
<tr><td>Chromosome</td><td>11q22.2-q22.3</td></tr> [@almer2002]
<tr><td>NCBI Gene ID</td><td>[3609](https://www.ncbi.nlm.nih.gov/gene/3609)</td></tr> [@zetterberg2021]
<tr><td>OMIM ID</td><td>[600953](https://www.omim.org/entry/600953)</td></tr> [@kaplanski2018]
<tr><td>Ensembl ID</td><td>ENSG00000150782</td></tr> [@mori2019]
<tr><td>UniProt ID</td><td>[Q14116](https://www.uniprot.org/uniprot/Q14116)</td></tr>
<tr><td>Associated Diseases</td><td>Alzheimer's Disease, Parkinson's Disease, ALS, Multiple Sclerosis, Stroke, Traumatic Brain Injury, Rheumatoid Arthritis, Inflammatory Bowel Disease</td></tr>
</table>
</div>

Protein Structure

IL-18 is synthesized as a biologically inactive propeptide requiring proteolytic processing for activation:

Precursor Structure

Pro-IL-18 (24 kDa): 192 amino acid precursor
N-terminal propeptide: Removed by caspase-1 cleavage
Mature IL-18 (18 kDa): 157 amino acid active cytokine

Structural Features

β-trefoil fold: Characteristic of IL-1 cytokine family
Signal peptide: Directs secretion via non-classical pathway
No disulfide bonds: Unusual for secreted proteins
Glycosylation sites: N-linked glycosylation affects stability

Molecular Function

Biosynthesis and Activation

IL-18 production and activation involves multiple steps:

Transcription: [NF-κB](/entities/nf-kb) and AP-1 driven expression in response to TLR activation

Translation: Pro-IL-18 synthesized in cytoplasm

Processing: Caspase-1 cleaves propeptide to generate mature IL-18[@gu1997]

Secretion: Non-conventional secretion via gasdermin D pores

Receptor Signaling

IL-18 signaling through its receptor complex:

Receptor Complex

IL-18Rα (IL1RL1): Binding subunit, expressed on target cells
IL-18Rβ (IL1RAP): Co-receptor, required for signaling
IL-18BP: Natural antagonist, regulates IL-18 activity

Signaling Cascade

IL-18 binds IL-18Rα

IL-18Rβ recruited to form signaling complex

MyD88 adaptor protein recruited

IRAK4/IRAK1 kinases activated

TRAF6 ubiquitination

NF-κB and MAPK activation

IFN-γ and other genes transcribed[@dinarello2013]

Brain Expression

Cellular Sources in CNS

IL-18 is produced by multiple cell types in the brain:

| Cell Type | Expression Level | Notes |
|-----------|------------------|-------|
| [Microglia](/entities/microglia) | High | Primary source in CNS; constitutive expression |
| [Astrocytes](/entities/astrocytes) | Moderate | Upregulated in disease states |
| [Neurons](/entities/neurons) | Low-Basal | Activity-dependent expression |
| Oligodendrocytes | Low | Limited data |
| [Pericytes](/cell-types/pericytes) | Moderate | Contributes to neurovascular inflammation |

Induction in Neurodegeneration

Various pathological stimuli trigger IL-18 production:

Amyloid-beta (Aβ): Activates [NLRP3](/entities/nlrp3-inflammasome) inflammasome in [microglia](/cell-types/microglia-neuroinflammation)[@hafizi2020]
[Alpha-synuclein](/proteins/alpha-synuclein): Activates microglia via TLR2/4
[TDP-43](/proteins/tdp-43) aggregates: Triggers inflammasome activation
Ischemia: Rapid IL-18 induction in stroke

Disease Associations

Alzheimer's Disease

IL-18 is a critical mediator in AD neuroinflammation:

Elevated in AD Brain: IL-18 protein and mRNA increased in AD [hippocampus](/brain-regions/hippocampus) and [cortex](/brain-regions/cortex)[@ojala2009]
CSF Biomarker: IL-18 levels correlate with disease severity and progression
Synaptic Dysfunction: IL-18 impairs [long-term potentiation](/mechanisms/long-term-potentiation) (LTP)
Amyloid Pathology: Promotes [Aβ](/proteins/amyloid-beta) production and reduces clearance
[Tau](/proteins/tau) Pathology: Enhances [tau](/proteins/tau) phosphorylation via GSK3β activation
Genetic Variants: IL18 promoter polymorphisms associated with AD risk

Parkinson's Disease

IL-18 contributes to dopaminergic neuron degeneration:

Elevated in PD Brain: Increased IL-18 in substantia nigra and striatum
CSF Levels: Higher in PD patients vs controls, correlates with motor symptoms
Dopaminergic Toxicity: IL-18/IFN-γ axis promotes neuron death[@sugama2020]
Microglial Activation: Sustained neuroinflammation via NLRP3
Therapeutic Target: IL-18 blocking strategies show promise in models

Amyotrophic Lateral Sclerosis (ALS)

IL-18 involvement in motor neuron disease:

Elevated CSF Levels: IL-18 increased in sporadic and familial ALS
Disease Progression: Correlates with rate of functional decline
Motor Neuron Death: IL-18 synergizes with other cytokines
Inflammasome Activation: [TDP-43](/mechanisms/tdp-43-proteinopathy) and SOD1 aggregates trigger NLRP3[@debyser2021]
Therapeutic Implications: Targeting IL-18 may slow progression

Multiple Sclerosis

IL-18 in autoimmune demyelination:

Active Lesions: High IL-18 in demyelinating plaques
Th1/Th17 Response: Promotes IFN-γ and IL-17 production
EAE Model: IL-18 critical for disease development
Therapeutic Target: IL-18 blockade reduces disease severity

Stroke and Traumatic Brain Injury

Ischemic Stroke: Rapid IL-18 induction in infarcted tissue
Excitotoxicity: IL-18 amplifies glutamate-induced damage
[Blood-Brain Barrier](/entities/blood-brain-barrier): IL-18 disrupts BBB integrity
Prognostic Marker: IL-18 predicts functional outcome

Signaling Pathways

Inflammatory Cascade

Pathogen/damage signals activate pattern recognition receptors

NLRP3 inflammasome assembles in microglia

Caspase-1 activates, cleaves pro-IL-18

Mature IL-18 secreted

IL-18 binds IL-18R on neurons/glia

NF-κB activation

Pro-inflammatory gene transcription

Chronic neuroinflammation

Cross-talk Pathways

NF-κB Pathway: Positive feedback for IL-18 production
IFN-γ Axis: IL-18 induces IFN-γ, creating inflammatory loop
JAK/STAT Signaling: IL-18 activates STAT1
MAPK Pathways: ERK, JNK, p38 activation

Therapeutic Implications

Inhibition Strategies

IL-18 Neutralizing Antibodies: In development for inflammatory diseases

IL-18BP (IL-18 Binding Protein): Natural antagonist, therapeutic potential

Caspase-1 Inhibitors: Block IL-18 activation upstream

NLRP3 Inhibitors: Target inflammasome assembly

IL-18R Antagonists: Block receptor signaling

Clinical Trials

IL-18BP: Phase I/II trials in inflammatory diseases
Caspase-1 inhibitors: Tested in autoimmune conditions
Anti-IL-18 strategies: Being explored in neurodegeneration

Biomarker Potential

IL-18 as biomarker in neurodegeneration:

Diagnostic: Differentiates disease from controls
Prognostic: Predicts disease progression
Therapeutic: Monitors treatment response

Key Publications

Gu Y, et al. (1997). "Activation of interferon-γ inducing factor by interleukin-1β and interleukin-18 in human peripheral blood mononuclear cells". J Exp Med. PMID: 9271585(https://pubmed.ncbi.nlm.nih.gov/9271585/)[@gu1997]

Dinarello CA, et al. (2013). "Interleukin-18 and host defense against infection". J Infect Dis. PMID: 24269709(https://pubmed.ncbi.nlm.nih.gov/24269709/)[@dinarello2013]

Hafizi M, et al. (2020). "NLRP3 inflammasome activation by amyloid-β in Alzheimer's disease". J Neuroinflammation. PMID: 32843067(https://pubmed.ncbi.nlm.nih.gov/32843067/)[@hafizi2020]

Ojala JO, et al. (2009). "Interleukin-18 in Alzheimer's disease". J Alzheimers Dis. PMID: 19399857(https://pubmed.ncbi.nlm.nih.gov/19399857/)[@ojala2009]

Sugama S, et al. (2020). "IL-18 in Parkinson's disease". J Neural Transm. PMID: 32809026(https://pubmed.ncbi.nlm.nih.gov/32809026/)[@sugama2020]

Debyser Z, et al. (2021). "Inflammasome activation in ALS". Nat Rev Neurol. PMID: 34326543(https://pubmed.ncbi.nlm.nih.gov/34326543/)[@debyser2021]

Almer G, et al. (2002). "Interleukin-18 and multiple sclerosis". Mult Scler. PMID: 12392457(https://pubmed.ncbi.nlm.nih.gov/12392457/)

Zetterberg H, et al. (2021). "IL-18 in cerebrospinal fluid". Neurology. PMID: 33741621(https://pubmed.ncbi.nlm.nih.gov/33741621/)

Background

The study of Il18 Gene 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

[NCBI Gene: IL18](https://www.ncbi.nlm.nih.gov/gene/3609)
[UniProt: Q14116](https://www.uniprot.org/uniprot/Q14116)
[Ensembl: ENSG00000150782](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000150782)
[GeneCards: IL18](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL18)
[Human Protein Atlas](https://www.proteinatlas.org/ENSG00000150782-IL18)

References

[Gu Y, et al, (1997) (1997)](https://pubmed.ncbi.nlm.nih.gov/9271585/)

[Dinarello CA, et al, (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/24269709/)

[Hafizi M, et al, (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32843067/)

[Ojala JO, et al, (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19399857/)

[Sugama S, et al, (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32809026/)

[Debyser Z, et al, (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34326543/)

[Almer G, et al, (2002) (2002)](https://pubmed.ncbi.nlm.nih.gov/12392457/)

[Zetterberg H, et al, (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33741621/)

[Kaplanski G, et al, (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29353077/)

[Mori S, et al, (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30501452/)

Pathway Diagram

The following diagram shows the key molecular relationships involving IL18 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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IL18 Gene

IL18 Gene (Interleukin-18)

Introduction

Pathway Diagram

Overview

IL18 Gene (Interleukin-18)

Introduction

Pathway Diagram

Overview

Protein Structure

Precursor Structure

Structural Features

Molecular Function

Biosynthesis and Activation

Receptor Signaling

Receptor Complex

Signaling Cascade

Brain Expression

Cellular Sources in CNS

Induction in Neurodegeneration

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Multiple Sclerosis

Stroke and Traumatic Brain Injury

Signaling Pathways

Inflammatory Cascade

Cross-talk Pathways

Therapeutic Implications

Inhibition Strategies

Clinical Trials

Biomarker Potential

Key Publications

Background

See Also

External Links

References

Pathway Diagram