IL6ST (gp130) - Interleukin 6 Signal Transducer
Pathway Diagram
Mermaid diagram (expand to render)
Overview
Il6St Interleukin 6 Signal Transducer (Gp130) plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
<table class="infobox infobox-gene"> [@principles2003]
<tr> [@leukemia2015]
<th class="infobox-header" colspan="2">IL6ST / gp130</th> [@neuropoietic2007]
</tr> [@interleukin1997]
<tr> [@cntf1999]
<td class="label">Gene Symbol</td> [@cytokines2004]
<td><strong>IL6ST</strong></td> [@cytokines2009]
</tr>
<tr>
<td class="label">Full Name</td>
<td>Interleukin 6 Signal Transducer</td>
</tr>
<tr>
<td class="label">Alias</td>
<td>gp130, CD130</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/3572" target="_blank">3572</a></td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td><a href="https://www.uniprot.org/uniprot/P40189" target="_blank">P40189</a></td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>5q11.2</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Type I Cytokine Receptor</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~130 kDa</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitous (neurons, astrocytes, [microglia](/cell-types/microglia-neuroinflammation), oligodendrocytes)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">54 edges</a></td>
</tr>
</table>
Introduction
IL6ST (Interleukin 6 Signal Transducer), commonly known as gp130, is the founding member and signal-transducing subunit of the interleukin-6 (IL-6) family of cytokines. This ubiquitous signaling receptor is essential for mediating the effects of at least nine different cytokines, making it a central hub for cytokine signaling in the immune system and central nervous system. gp130 plays critical roles in neural development, synaptic plasticity, neuroinflammation, and neuron survival, with implications for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS)[@interleukin1989].
Gene Structure and Expression
Genomic Organization
The IL6ST gene is located on chromosome 5q11.2 and spans approximately 28 kb. The gene consists of 18 exons that encode the 917-amino acid protein. Multiple alternatively spliced isoforms have been identified, including a soluble form that can act as a natural antagonist[@principles2003].
Protein Domain Architecture
gp130 contains multiple functional domains:
Extracellular Domain (~600 aa)
- Six fibronectin type III (FNIII) repeats
- An immunoglobulin-like (Ig) domain at the N-terminus
- Three cytokine-binding domains (CBDs)
- The membrane-proximal domains are critical for signal transduction
Transmembrane Domain (~22 aa)
- Single pass α-helical transmembrane segment
Intracellular Domain (~277 aa)
- Box 1 and Box 2 motifs for JAK binding
- Multiple tyrosine residues for STAT recruitment
- Contains no intrinsic kinase activity
Ligand-Receptor Interactions
IL-6 Family Cytokines Signaling Through gp130
gp130 serves as the common signal-transducing subunit for multiple cytokines:
| Cytokine | Primary Receptor | Biological Function |
|----------|-----------------|---------------------|
| IL-6 | IL6Rα | Acute phase response, B cell differentiation |
| IL-11 | IL11Rα | Platelet production, bone remodeling |
| LIF | LIFR | Motor neuron survival, neural stem cell maintenance |
| CNTF | CNTFRα | Motor neuron survival, astrocyte differentiation |
| OSM | OSMR | Stromal cell activation, inflammation |
| CT-1 | LIFR | Cardiac development, neuroprotection |
| NP (Cardiotrophin-1-like) | LIFR | Neuroprotection |
| IL-27 | IL27RA/WSX-1 | T cell differentiation, inflammation |
| IL-35 | IL12RB1/IL27RA | Immunosuppression |
All IL-6 family cytokines signal through a two-receptor system:
Ligand-specific α-receptor: Binds cytokine with low affinity
gp130: Recruited to form high-affinity signaling complex
Homodimerization: Two gp130 subunits (or gp130 + LIFR) form the active signaling complexSignal Transduction Pathways
JAK/STAT Pathway (Primary)
The JAK/STAT pathway is the principal signaling cascade:
JAK Activation: JAK1 and JAK2 are constitutively associated with gp130 intracellular domain
Tyrosine Phosphorylation: Ligand binding triggers autophosphorylation of JAKs
STAT Recruitment: STAT1 and STAT3 SH2 domains bind to phosphotyrosine motifs on gp130
STAT Phosphorylation: JAKs phosphorylate STAT1 (Tyr701) and STAT3 (Tyr705)
Dimerization: Phosphorylated STATs form parallel dimers
Nuclear Translocation: STAT dimers enter the nucleus
Gene Transcription: STAT dimers bind to γ-interferon activation sites (GAS) and STAT-responsive elementsPI3K/Akt Pathway
gp130 also activates pro-survival signaling:
- p85 Recruitment: Adaptor protein binds to phosphotyrosines on gp130
- PIP3 Generation: PI3K converts PIP2 to PIP3
- Akt Activation: PDK1 phosphorylates Akt on Thr308
- Pro-survival Effects: Akt phosphorylates BAD, caspase-9, and FoxO transcription factors
MAPK/ERK Pathway
Differentiation and growth signals:
- GRB2/SOS Recruitment: Adaptor proteins bind to phosphorylated gp130
- Ras Activation: SOS promotes Ras-GTP formation
- Kinase Cascade: Raf → MEK → ERK activation
- Cellular Effects: ERK promotes cell proliferation and differentiation
Biological Functions in the Nervous System
Neural Development
gp130 signaling is essential for nervous system development:
- Neural Tube Formation: Required for early neural patterning
- Motor Neuron Development: Critical for embryonic motor neuron survival
- Astrocyte Differentiation: Promotes astrogliogenesis in late development
- Synaptogenesis: Regulates synaptic formation and maintenance
Adult Brain Function
In the mature nervous system, gp130 continues to play important roles:
Synaptic Plasticity
- Hippocampal [LTP](/mechanisms/long-term-potentiation): gp130 signaling modulates [long-term potentiation](/mechanisms/long-term-potentiation)
- Learning and Memory: Required for certain forms of memory consolidation
- Dendritic Spine Dynamics: Regulates spine formation and maintenance
Neuroprotection
- Anti-apoptotic Effects: Blocks intrinsic and extrinsic apoptotic pathways
- Oxidative Stress: Upregulates antioxidant defenses
- Metabolic Support: Enhances glucose metabolism and mitochondrial function
Neuroinflammation
- Microglial Activation: Mediates cytokine-induced microglial responses
- Astrocyte Reactivity: Controls reactive astrogliosis in injury and disease
- Inflammatory Resolution: Helps terminate inflammatory responses
Glial Cell Functions
Astrocytes
- Reactive Astrogliosis: IL-6/gp130 signaling drives astrocyte reactivity
- Neurotrophic Support: [Astrocytes](/entities/astrocytes) secrete cytokines that signal through gp130
- [Blood-Brain Barrier](/entities/blood-brain-barrier): Regulates BBB integrity and function
Microglia
- Pro-inflammatory Signaling: IL-6/gp130 promotes microglial activation
- Phagocytosis: Modulates clearance of debris and pathogens
- Neurotoxicity: Can mediate inflammatory neurotoxicity when chronic
Oligodendrocytes
- Differentiation: gp130 signaling influences oligodendrocyte maturation
- Myelin Maintenance: Required for mature oligodendrocyte function
- Remyelination: Important for repair processes in demyelinating diseases
Disease Associations
Alzheimer's Disease
gp130 signaling has complex and context-dependent effects in AD:
Neuroinflammation
- Chronic IL-6 Signaling: Elevated IL-6 in AD brain promotes neuroinflammation
- Microglial Activation: gp130-mediated signaling enhances microglial reactivity
- Synaptic Dysfunction: Inflammatory signaling through gp130 can impair synaptic function
Neuroprotection
- Acute Neuroprotection: Short-term gp130 activation can be protective
- Neurotrophic Support: LIF/CNTF signaling via gp130 supports [neurons](/entities/neurons)
- Therapeutic Potential: Balanced gp130 modulation may be beneficial
Therapeutic Implications
- Targeting Strategies: Selective modulation of gp130 pathways
- Combination Approaches: gp130 signaling with other therapeutic targets
- Biomarkers: Soluble gp130 as potential biomarker
Parkinson's Disease
gp130 plays roles in PD pathogenesis:
Dopaminergic Neurons
- Survival Signaling: gp130 pathways can protect dopaminergic neurons
- Neuroinflammation: IL-6/gp130 contributes to chronic neuroinflammation
- Mitochondrial Function: Modulates mitochondrial quality control
Glial Contributions
- Astrocyte Reactivity: Reactive astrocytes signal through gp130
- Microglial Activation: Chronic microglial activation mediated by gp130
- Neuroinflammation: Contributes to progressive dopaminergic neuron loss
Amyotrophic Lateral Sclerosis (ALS)
gp130 signaling is particularly relevant to ALS:
Motor Neuron Survival
- LIF/CNTF Signaling: Both signal through gp130 and support motor neurons
- Neuroprotective Effects: Activation can protect against excitotoxicity
- Therapeutic Potential: gp130 agonists being explored
Therapeutic Approaches
- Gene Therapy: AAV-mediated delivery of LIF or CNTF
- Small Molecule Activators: Direct gp130 pathway activators
- Combination Therapy: gp130 activation with other trophic factors
Multiple Sclerosis
gp130 signaling has dual roles in MS:
Demyelination
- IL-6 in Lesions: IL-6 is elevated in MS plaques
- Oligodendrocyte Toxicity: Chronic signaling may damage oligodendrocytes
- Autoimmunity: IL-6/gp130 promotes Th17 differentiation
Remyelination
- Astrocyte Support: Reactive astrocytes signal through gp130
- Neural Repair: Promotes neural stem cell activation
- Remyelination: Can support oligodendrocyte precursor differentiation
Stüve-Wiedemann Syndrome
This severe disorder involves gp130 pathway dysfunction:
- LIFR Mutations: Impair complex formation with gp130
- gp130 Signaling: Reduced STAT3 activation
- Phenotype: Severe neurological and skeletal abnormalities
Stroke and Brain Injury
Following ischemic injury, gp130 signaling is activated:
- Acute Phase: Rapid upregulation of IL-6 and gp130
- Neuroprotection: Endogenous protective response
- Repair Phase: Supports neural stem cell activation
Therapeutic Targeting
Agonists
| Agent | Target Cytokine | Status | Indication |
|-------|----------------|--------|------------|
| Recombinant IL-6 | IL-6R/gp130 | Research | Neuroprotection |
| Recombinant LIF | LIFR/gp130 | Preclinical | ALS, stroke |
| Recombinant CNTF | CNTFRα/gp130 | Research | Motor neuron disease |
| Hyper-IL-6 | IL-6R/gp130 | Preclinical | Neuroinflammation |
Antagonists
| Agent | Mechanism | Status | Indication |
|-------|-----------|--------|------------|
| Tocilizumab | IL-6R antibody | Approved | Rheumatoid arthritis |
| Sarilumab | IL-6R antibody | Approved | Rheumatoid arthritis |
| Soluble gp130 | Decoy receptor | Research | Chronic inflammation |
Gene Therapy
- AAV-LIF: Gene therapy for motor neuron diseases
- AAV-CNTF: Trophic support for neurons
- AAV-sIL6R: Soluble IL-6R blockade
Animal Models
Knockout Mice
- IL6ST−/− Mice: Embryonic lethal - die around E12.5-16.5
- Conditional Knockouts: Tissue-specific study of gp130 function
- Motor Phenotype: Severe motor neuron deficiency
Transgenic Models
- IL-6 Overexpression: Neuroinflammation model
- LIF Overexpression: Neuroprotection in injury models
Key Publications
[@interleukin1989] Taga T, Hibi M, Hirata Y, et al. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. EMBO J. 1989;8(10):2859-2865.
[@principles2003] Heinrich PC, Behrmann I, Haan S, et al. Principles of IL-6-type cytokine signalling. Biochem J. 2003;374(Pt 1):1-20.
[@leukemia2015] Nicola NA, Babon JJ. Leukemia inhibitory factor (LIF). Growth Factors. 2015;33(6):407-418.
[@neuropoietic2007] Bauer S, Kerr BJ, Patterson PH. The neuropoietic cytokine family in development, plasticity, and disease. Brain Res Rev. 2007;55(1):4-13.
[@interleukin1997] Gadient RA, Otten U. Interleukin-6 (IL-6): a molecule with both beneficial and destructive potentials. Prog Neurobiol. 1997;52(5):379-390.
[@cntf1999] Murphy PG, Borthwick LS, Altmon M, et al. CNTF receptor alpha is expressed by astrocytes in the adult mouse brain. Glia. 1999;27(1):43-50.
[@cytokines2004] Kerr BJ, Patterson PH. Cytokines as mediators of CNS disease. Mol Neurobiol. 2004;29(2):155-166.
[@cytokines2009] Deverman BE, Patterson PH. Cytokines and CNS development. Neuron. 2009;64(1):61-78.See Also
- [LIF Gene](/proteins/lif-protein)
- [CNTF Gene](/proteins/cntf-protein)
- [LIFR Gene](/proteins/lifr-protein)
- [IL6 Gene](/proteins/il6-protein)
- [JAK/STAT Signaling Pathway](/mechanisms/jak-stat-signaling)mechanisms/jak-stat-signaling-neurodegeneration)
- [Motor Neurons](/cell-types/motor-neurons)
- [Astrocytes](/cell-types/astrocytes)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
- [Multiple Sclerosis](/diseases/multiple-sclerosis)
- [Neurotrophic Factors](/mechanisms/neurotrophic-factors)
- [Neuroinflammation](/mechanisms/neuroinflammation-pathway)
External Links
- [NCBI Gene: IL6ST](https://www.ncbi.nlm.nih.gov/gene/3572)
- [UniProt: P40189](https://www.uniprot.org/uniprot/P40189)
- [OMIM: 147719](https://www.omim.org/entry/147719)
- [GeneCards: IL6ST](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL6ST)
- [Human Protein Atlas: IL6ST](https://www.proteinatlas.org/ENSG00000128604-IL6ST)
- [GTEx Portal: IL6ST](https://gtexportal.org/home/gene/IL6ST)
Overview
Il6St Interleukin 6 Signal Transducer (Gp130) plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
Background
The study of Il6St Interleukin 6 Signal Transducer (Gp130) 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.
References
[^1] Taga T, Hibi M, Hirata Y, et al, Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130 (1989)
[^2] Heinrich PC, Behrmann I, Haan S, et al, Principles of IL-6-type cytokine signalling (2003)
[^3] Nicola NA, Babon JJ, Leukemia inhibitory factor (LIF) (2015)
[^4] Bauer S, Kerr BJ, Patterson PH, The neuropoietic cytokine family in development, plasticity, and disease (2007)
[^5] Gadient RA, Otten U, Interleukin-6 (IL-6): a molecule with both beneficial and destructive potentials (1997)
[^6] Murphy PG, Borthwick LS, Altmon M, et al, CNTF receptor alpha is expressed by astrocytes in the adult mouse brain (1999)
[^7] Kerr BJ, Patterson PH, Cytokines as mediators of CNS disease (2004)
[^8] Deverman BE, Patterson PH, Cytokines and CNS development (2009)Pathway Diagram
The following diagram shows the key molecular relationships involving IL6ST - Interleukin 6 Signal Transducer (gp130) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)