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.
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.
| IL18 - Interleukin-18 |
|---|
| Full Name | Interleukin-18 |
| Chromosome | 11q22.2-q22.3 |
| NCBI Gene ID | 3609 |
| OMIM ID | 600953 |
| Ensembl ID | ENSG00000150782 |
| UniProt ID | Q14116 |
| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, ALS, Multiple Sclerosis, Stroke, Traumatic Brain Injury, Rheumatoid Arthritis, Inflammatory Bowel Disease |
IL-18 is synthesized as a biologically inactive propeptide requiring proteolytic processing for activation:
- 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
- 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
¶ Biosynthesis and Activation
IL-18 production and activation involves multiple steps:
- Transcription: NF-κB 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[1]
- Secretion: Non-conventional secretion via gasdermin D pores
IL-18 signaling through its 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
- 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[2]
IL-18 is produced by multiple cell types in the brain:
| Cell Type |
Expression Level |
Notes |
| Microglia |
High |
Primary source in CNS; constitutive expression |
| Astrocytes |
Moderate |
Upregulated in disease states |
| Neurons |
Low-Basal |
Activity-dependent expression |
| Oligodendrocytes |
Low |
Limited data |
| Pericytes |
Moderate |
Contributes to neurovascular inflammation |
Various pathological stimuli trigger IL-18 production:
- Amyloid-beta (Aβ): Activates NLRP3 inflammasome in microglia[3]
- Alpha-synuclein: Activates microglia via TLR2/4
- TDP-43 aggregates: Triggers inflammasome activation
- Ischemia: Rapid IL-18 induction in stroke
IL-18 is a critical mediator in AD neuroinflammation:
- Elevated in AD Brain: IL-18 protein and mRNA increased in AD hippocampus and cortex[4]
- CSF Biomarker: IL-18 levels correlate with disease severity and progression
- Synaptic Dysfunction: IL-18 impairs long-term potentiation (LTP)
- Amyloid Pathology: Promotes Aβ production and reduces clearance
- Tau Pathology: Enhances tau phosphorylation via GSK3β activation
- Genetic Variants: IL18 promoter polymorphisms associated with AD risk
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[5]
- Microglial Activation: Sustained neuroinflammation via NLRP3
- Therapeutic Target: IL-18 blocking strategies show promise in models
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 and SOD1 aggregates trigger NLRP3[6]
- Therapeutic Implications: Targeting IL-18 may slow progression
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: IL-18 disrupts BBB integrity
- Prognostic Marker: IL-18 predicts functional outcome
- 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
- 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
- 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
- IL-18BP: Phase I/II trials in inflammatory diseases
- Caspase-1 inhibitors: Tested in autoimmune conditions
- Anti-IL-18 strategies: Being explored in neurodegeneration
IL-18 as biomarker in neurodegeneration:
- Diagnostic: Differentiates disease from controls
- Prognostic: Predicts disease progression
- Therapeutic: Monitors treatment response
- 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[1]
- Dinarello CA, et al. (2013). "Interleukin-18 and host defense against infection". J Infect Dis. PMID:24269709[2]
- Hafizi M, et al. (2020). "NLRP3 inflammasome activation by amyloid-β in Alzheimer's disease". J Neuroinflammation. PMID:32843067[3]
- Ojala JO, et al. (2009). "Interleukin-18 in Alzheimer's disease". J Alzheimers Dis. PMID:19399857[4]
- Sugama S, et al. (2020). "IL-18 in Parkinson's disease". J Neural Transm. PMID:32809026[5]
- Debyser Z, et al. (2021). "Inflammasome activation in ALS". Nat Rev Neurol. PMID:34326543[6]
- Almer G, et al. (2002). "Interleukin-18 and multiple sclerosis". Mult Scler. PMID:12392457
- Zetterberg H, et al. (2021). "IL-18 in cerebrospinal fluid". Neurology. PMID:33741621
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.
- 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. 186:1757-1762. PMID:9271585
- Dinarello CA, et al. (2013). Interleukin-18 and host defense against infection. J Infect Dis. 207:S331-S336. PMID:24269709
- Hafizi M, et al. (2020). NLRP3 inflammasome activation by amyloid-β in Alzheimer's disease. J Neuroinflammation. 17:250. PMID:32843067
- Ojala JO, et al. (2009). Interleukin-18 in Alzheimer's disease. J Alzheimers Dis. 16:571-584. PMID:19399857
- Sugama S, et al. (2020). IL-18 in Parkinson's disease. J Neural Transm. 127:1597-1605. PMID:32809026
- Debyser Z, et al. (2021). Inflammasome activation in ALS. Nat Rev Neurol. 17:389-403. PMID:34326543
- Almer G, et al. (2002). Interleukin-18 and multiple sclerosis. Mult Scler. 8:359-364. PMID:12392457
- Zetterberg H, et al. (2021). IL-18 in cerebrospinal fluid as biomarker in neurodegenerative diseases. Neurology. 97:e1342-e1353. PMID:33741621
- Kaplanski G, et al. (2018). IL-18: From autoimmunity to atherosclerosis. Autoimmun Rev. 17:226-236. PMID:29353077
- Mori S, et al. (2019). Interleukin-18 in traumatic brain injury. J Neurotrauma. 36:1521-1531. PMID:30501452