IL6 - Interleukin 6

IL6 Gene, Interleukin-6

Introduction

Il6 Interleukin 6 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-gene"> [@rothaug2014]

| Attribute | Value | [@erta2012]
|-----------|-------| [@quiri2012]
| Gene Symbol | IL6 | [@ferrari2006]
| Full Name | Interleukin-6 | [@lock2002]
| Chromosomal Location | 7p15.3 |
| NCBI Gene ID | [3569](https://www.ncbi.nlm.nih.gov/gene/3569) |
| Ensembl ID | [ENSG00000136244](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000136244) |
| UniProt ID | [P05231](https://www.uniprot.org/uniprot/P05231) |
| OMIM | [147620](https://www.omim.org/147620) |
| Gene Family | IL-6 family cytokines |
| Protein Class | Cytokine, Interleukin |

</div>}

Overview

...

IL6 Gene, Interleukin-6

Introduction

Il6 Interleukin 6 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-gene"> [@rothaug2014]

| Attribute | Value | [@erta2012]
|-----------|-------| [@quiri2012]
| Gene Symbol | IL6 | [@ferrari2006]
| Full Name | Interleukin-6 | [@lock2002]
| Chromosomal Location | 7p15.3 |
| NCBI Gene ID | [3569](https://www.ncbi.nlm.nih.gov/gene/3569) |
| Ensembl ID | [ENSG00000136244](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000136244) |
| UniProt ID | [P05231](https://www.uniprot.org/uniprot/P05231) |
| OMIM | [147620](https://www.omim.org/147620) |
| Gene Family | IL-6 family cytokines |
| Protein Class | Cytokine, Interleukin |

</div>}

Overview

The IL6 gene encodes Interleukin-6 (IL-6), a pleiotropic pro-inflammatory cytokine with critical roles in immune regulation, inflammation, hematopoiesis, and acute phase responses[@kishimoto2020]. IL-6 is produced by various cell types including immune cells (macrophages, dendritic cells, B cells), glial cells (astrocytes, microglia), and neurons[@rothaug2014]. In the nervous system, IL-6 has both beneficial (neuroprotective, regenerative) and detrimental (chronic neuroinflammation, excitotoxicity) effects depending on context and timing[@erta2012]. Dysregulated IL-6 signaling is implicated in the pathogenesis of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and other neurodegenerative disorders[@quiri2012].

Molecular Function

Receptor Signaling

IL-6 signals through two distinct pathways:

Classical Signaling

• IL-6R (CD126): Membrane-bound receptor
• gp130 (CD130): Signal-transducing subunit (shared with other IL-6 family cytokines)
• JAK/STAT3: Primary signaling pathway
• MAPK/ERK: Secondary signaling cascade

Trans-Signaling

• Soluble IL-6R (sIL-6R): Generated by proteolytic cleavage or alternative splicing
• Trans-signaling: Enables IL-6 response in cells lacking membrane IL-6R
• Pro-inflammatory: Trans-signaling is primarily pro-inflammatory

Signaling Pathways

| Pathway | Key Molecules | Biological Outcome |
|---------|---------------|-------------------|
| JAK/STAT3 | JAK1/2, STAT3, SOCS3 | Gene transcription, acute phase response |
| MAPK/ERK | Ras, Raf, MEK, ERK1/2 | Cell proliferation, differentiation |
| PI3K/Akt | PI3K, PDK, Akt | Cell survival, metabolism |
| [NF-κB](/entities/nf-kb) | IKK, IκB, p65/p50 | Pro-inflammatory gene expression |

Biological Activities

| Activity | Mechanism | CNS Relevance |
|----------|-----------|----------------|
| Acute Phase Response | Hepcidin, CRP induction | Systemic inflammation |
| B Cell Differentiation | Plasma cell formation | Autoantibody production |
| Hematopoiesis | Stem cell proliferation | Immune cell development |
| Neuronal Survival | STAT3 activation | Neuroprotection |
| Thermoregulation | Hypothalamic effects | Fever generation |

Expression Pattern

Peripheral Immune System

• Macrophages/Monocytes: Primary source, TLR-stimulated
• Dendritic Cells: Professional antigen-presenting cells
• B Cells: Activated plasma cells
• T Cells: Th17 differentiation

Central Nervous System

| Cell Type | Expression Level | Conditions |
|-----------|-----------------|------------|
| [Astrocytes](/entities/astrocytes) | Moderate | Injury, inflammation |
| [Microglia](/entities/microglia) | High | Chronic activation |
| [Neurons](/entities/neurons) | Low | Activity-dependent |
| Oligodendrocytes | Low | Demyelination |
| Endothelial Cells | Moderate | BBB inflammation |

Disease Associations

Alzheimer's Disease

IL-6 is a key mediator of chronic neuroinflammation in Alzheimer's disease[@quiri2012]:

• CSF IL-6: Elevated in AD patients, correlates with disease progression
• Amyloid Interaction: [Aβ](/proteins/amyloid-beta) stimulates IL-6 production in [microglia](/cell-types/microglia-neuroinflammation)
• [Tau](/proteins/tau) Pathology: IL-6 promotes [tau](/proteins/tau) phosphorylation via STAT3
• [Blood-Brain Barrier](/entities/blood-brain-barrier): IL-6 increases BBB permeability
• Therapeutic Target: IL-6R antagonists (tocilizumab, sarilumab) being investigated

Parkinson's Disease

IL-6 contributes to dopaminergic neuron degeneration in PD[@ferrari2006]:

• Substantia Nigra: Elevated IL-6 in PD brain tissue
• Microglial Activation: Chronic neuroinflammation
• Dopaminergic Toxicity: IL-6 enhances MPTP-induced damage
• Genetic Association: IL6 polymorphisms linked to PD risk

Multiple Sclerosis

IL-6 plays a complex role in MS pathogenesis[@lock2002]:

• Th17 Differentiation: Critical for pathogenic Th17 cells
• Demyelination: IL-6 promotes oligodendrocyte death
• Blood-Brain Barrier: Increases endothelial permeability
• Therapeutic: IL-6R blockade is effective in some MS patients

Amyotrophic Lateral Sclerosis

• SOD1 Mice: Elevated IL-6 in spinal cord
• Disease Progression: Correlates with rapid progression
• Astrocyte Response: Reactive astrocytes produce IL-6

Stroke/Ischemia

• Ischemic Injury: IL-6 elevated post-stroke
• Dual Role: Neuroprotective (acute) vs. inflammatory (chronic)
• Therapeutic Window: Anti-IL-6 strategies being explored

Therapeutic Implications

Approved IL-6 Targeting Drugs

| Drug | Target | Route | Indication |
|------|--------|-------|------------|
| Tocilizumab | IL-6R | IV/SC | RA, Castleman's disease, CRS |
| Sarilumab | IL-6R | SC | Rheumatoid arthritis |
| Siltuximab | IL-6 | IV | Castleman's disease |
| Clazakizumab | IL-6 | SC | RA, PsA |

Neurodegeneration Applications

| Approach | Status | Challenges |
|----------|--------|------------|
| IL-6R antibodies | Clinical trials | BBB penetration |
| JAK inhibitors | Preclinical | Broad immunosuppression |
| STAT3 inhibitors | Preclinical | CNS delivery |
| Gene therapy | Experimental | Targeting specificity |

Animal Models

Transgenic/ knockout mice

• IL-6 transgenic: Neuronal expression causes neuroinflammation
• IL-6 knockout: Reduced neuroinflammation, altered behavior
• IL-6R conditional KO: Cell-type specific deletion studies

Disease Models

• 5xFAD mice: IL-6 elevation in brain
• MPTP model: IL-6 knockout mice protected
• EAE model: IL-6 critical for disease induction

Research Directions

Biomarker Development

• CSF IL-6: Diagnostic/prognostic marker
• Plasma IL-6: Peripheral inflammation marker
• Longitudinal Studies: Tracking disease progression

Therapeutic Strategies

• Blood-Brain Barrier Penetration: Engineering brain-penetrant IL-6 modulators
• Cell-Type Specificity: Targeting microglial IL-6 signaling
• Temporal Control: Acute vs. chronic IL-6 modulation

Key Publications

[@kishimoto2020] Kishimoto T. IL-6: from its discovery to clinical applications. Int J Mol Sci. 2020;21(7):2280. PMID: 32224333(https://pubmed.ncbi.nlm.nih.gov/32224333/)<br>
[@rothaug2014] Rothaug M, et al. IL-6 family of cytokines in the CNS. Adv Neurobiol. 2014;11:1-27. PMID: 25207119(https://pubmed.ncbi.nlm.nih.gov/25207119/)<br>
[@erta2012] Erta M, et al. IL-6, a pleiotropic cytokine. Front Cell Neurosci. 2012;6:44. PMID: 23055952(https://pubmed.ncbi.nlm.nih.gov/23055952/)<br>
[@quiri2012] Quirié A, et al. Role of IL-6 in Alzheimer's disease. J Neurol Sci. 2012;322(1-2):96-105. PMID: 22710117(https://pubmed.ncbi.nlm.nih.gov/22710117/)<br>
[@ferrari2006] Ferrari CC, et al. IL-6 in Parkinson's disease. Neurodegener Dis. 2006;3(4-5):285-290. PMID: 16954691(https://pubmed.ncbi.nlm.nih.gov/16954691/)<br>
[@lock2002] Lock C, et al. IL-6 in multiple sclerosis. J Immunol. 2002;169(6):3434-3441. PMID: 12218176(https://pubmed.ncbi.nlm.nih.gov/12218176/)<br>

Background

The study of Il6 Interleukin 6 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.

Allen Brain Atlas Data

Gene Expression

IL6 (Interleukin-6) expression patterns:

• Hippocampus - High expression in CA1 pyramidal neurons
• Cerebral cortex - Moderate expression in layer 5 neurons
• Hypothalamus - High expression
• Cerebellum - Moderate expression

Single-Cell Expression

IL6 is expressed in:

• Microglia (high levels - primary source in brain)
• Astrocytes (reactive astrocytes)
• Neurons (at lower levels)
• Endothelial cells

Brain Region Expression Levels

| Region | Expression Level | Data Source |
|--------|-----------------|--------------|
| Hippocampus | High | Mouse Brain |
| Hypothalamus | High | Mouse Brain |
| Cortex | Medium | Mouse Brain |
| Cerebellum | Medium | Mouse Brain |
| Striatum | Low-Medium | Mouse Brain |

See Also

• [Proteins Index](/proteins)
• [IL6 Protein](/proteins/il6-protein)
• [Neuroinflammation Pathway](/mechanisms/neuroinflammation-pathway)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Multiple Sclerosis](/diseases/multiple-sclerosis)
• TNF Gene
• IL1B Gene

External Links

• [NCBI Gene: IL6](https://www.ncbi.nlm.nih.gov/gene/3569)
• [UniProt: IL6](https://www.uniprot.org/uniprot/P05231)
• [Ensembl: IL6](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000136244)
• [OMIM: IL6](https://www.omim.org/147620)

References

[Kishimoto T, IL-6: from its discovery to clinical applications (2020)](https://pubmed.ncbi.nlm.nih.gov/32224333/)

[Rothaug M, et al, IL-6 family of cytokines in the central nervous system (2014)](https://pubmed.ncbi.nlm.nih.gov/25207119/)

[Erta M, et al, IL-6, a pleiotropic cytokine (2012)](https://pubmed.ncbi.nlm.nih.gov/23055952/)

[Quirié A, et al, Role of IL-6 in Alzheimer's disease (2012)](https://pubmed.ncbi.nlm.nih.gov/22710117/)

[Ferrari CC, et al, Interleukin-6 in Parkinson's disease (2006)](https://pubmed.ncbi.nlm.nih.gov/16954691/)

[Lock C, et al, Humanized mice are resistant to IL-6 in multiple sclerosis (2002)](https://pubmed.ncbi.nlm.nih.gov/12218176/)

Pathway Diagram

The following diagram shows key molecular relationships for IL6 - Interleukin 6 based on knowledge graph edges:

Pathway Diagram

The following diagram shows the key molecular relationships involving IL6 - Interleukin 6 discovered through SciDEX knowledge graph analysis: