IL6ST - Interleukin 6 Signal Transducer (gp130)

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IL6ST - Interleukin 6 Signal Transducer (gp130)

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IL6ST (gp130) - Interleukin 6 Signal Transducer

Pathway Diagram

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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>IL6ST</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 |

Receptor Complex Formation

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 complex

Signal 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 elements

PI3K/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.

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)

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Related Entities

IL6ST

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slug	genes-il6st
kg_node_id	IL6ST
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-a0f379d8d3a0
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-il6st'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

35%

Debates

0

Incoming

7

Outgoing

21

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

IL6ST - Interleukin 6 Signal Transducer (gp130)

IL6ST (gp130) - Interleukin 6 Signal Transducer

Pathway Diagram

IL6ST (gp130) - Interleukin 6 Signal Transducer

Pathway Diagram

Overview

Introduction

Gene Structure and Expression

Genomic Organization

Protein Domain Architecture

Ligand-Receptor Interactions

IL-6 Family Cytokines Signaling Through gp130

Receptor Complex Formation

Signal Transduction Pathways

JAK/STAT Pathway (Primary)

PI3K/Akt Pathway

MAPK/ERK Pathway

Biological Functions in the Nervous System

Neural Development

Adult Brain Function

Synaptic Plasticity

Neuroprotection

Neuroinflammation

Glial Cell Functions

Astrocytes

Microglia

Oligodendrocytes

Disease Associations

Alzheimer's Disease

Neuroinflammation

Neuroprotection

Therapeutic Implications

Parkinson's Disease

Dopaminergic Neurons

Glial Contributions

Amyotrophic Lateral Sclerosis (ALS)

Motor Neuron Survival

Therapeutic Approaches

Multiple Sclerosis

Demyelination

Remyelination

Stüve-Wiedemann Syndrome

Stroke and Brain Injury

Therapeutic Targeting

Agonists

Antagonists

Gene Therapy

Animal Models

Knockout Mice

Transgenic Models

Key Publications

See Also

External Links

Overview

Background

References

Pathway Diagram

💬 Discussion