IL-6R Protein

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IL-6R Protein

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Interleukin-6 Receptor (IL-6R)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">IL-6R Protein</th>
</tr>
<tr>
<td class="label">Drug</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Tocilizumab</td>
<td>IL-6R antibody</td>
</tr>
<tr>
<td class="label">Sarilumab</td>
<td>IL-6R antibody</td>
</tr>
<tr>
<td class="label">Satralizumab</td>
<td>IL-6R antibody</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">69 edges</a></td>
</tr>
</table>

Introduction

...

Interleukin-6 Receptor (IL-6R)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">IL-6R Protein</th>
</tr>
<tr>
<td class="label">Drug</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Tocilizumab</td>
<td>IL-6R antibody</td>
</tr>
<tr>
<td class="label">Sarilumab</td>
<td>IL-6R antibody</td>
</tr>
<tr>
<td class="label">Satralizumab</td>
<td>IL-6R antibody</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">69 edges</a></td>
</tr>
</table>

Introduction

The Interleukin-6 Receptor (IL-6R) is a critical cytokine receptor that plays a significant role in neuroinflammation, a key pathological feature of neurodegenerative diseases including Alzheimer's Disease (AD) and Parkinson's Disease (PD). [@ilr2023] IL-6R mediates the cellular response to interleukin-6 (IL-6), a pleiotropic cytokine that participates in both acute phase responses and chronic inflammatory processes. [@interleukin2022] The IL-6R signaling pathway has become an important therapeutic target, with tocilizumab (an IL-6R antagonist) showing promise in clinical trials for various neurological conditions. [@tocilizumab2023]

Overview

Interleukin-6 Receptor (IL-6R) is a transmembrane protein encoded by the IL6R gene on chromosome 1q21.3. [@ilr2021] It exists in two forms: a membrane-bound receptor (mIL-6R) of approximately 80 kDa and a soluble receptor (sIL-6R) generated by proteolytic cleavage or alternative splicing. [@soluble2022] The membrane-bound IL-6R is expressed on various cell types including hepatocytes, leukocytes, and certain neuronal populations, while the soluble form can bind IL-6 and trigger signaling in cells that express the signal-transducing subunit gp130 but lack IL-6R itself—a phenomenon known as trans-signaling. [@transsignaling2021]

The IL-6R pathway is particularly relevant to neurodegeneration because chronic neuroinflammation is a hallmark of both AD and PD. [@neuroinflammation2023] Elevated levels of IL-6 and sIL-6R have been detected in the cerebrospinal fluid (CSF) and post-mortem brain tissue of patients with AD and PD, suggesting that dysregulated IL-6 signaling contributes to disease progression. [@csf2022] Genetic studies have also identified IL6R variants as risk factors for AD, further supporting its pathogenic role. [@ilr2021a]

Structure

Extracellular Domain

The IL-6R extracellular domain consists of three distinct regions: [@crystal2020]

N-terminal Ig-like domain (D1): Involved in IL-6 binding specificity

Two fibronectin type III domains (D2, D3): Form the core IL-6 binding interface

Proline-rich hinge region: Provides flexibility for ligand binding

Transmembrane and Cytoplasmic Domains

Transmembrane helix: Single 28-amino acid hydrophobic segment anchors the receptor
Cytoplasmic tail: Short 82-amino acid domain lacks intrinsic kinase activity but recruits signaling proteins

Soluble IL-6R (sIL-6R)

The soluble form (~55 kDa) retains the extracellular domain and can: [@adammediated2022]

Bind IL-6 with similar affinity as membrane-bound receptor
Form a complex with IL-6 that activates gp130-expressing cells
Be generated by ADAM17-mediated proteolytic shedding (ectodomain shedding)

Normal Physiological Functions

Acute Phase Response

IL-6R signaling is essential for hepatic acute phase protein synthesis: [@acute2021]

Stimulates production of C-reactive protein (CRP)
Induces fibrinogen and serum amyloid A
Modulates body temperature during infection

Immune Cell Differentiation

IL-6R plays crucial roles in immune cell differentiation: [@ilr2023a]

Th17 differentiation: IL-6R signaling promotes Th17 cell development
B cell maturation: Supports plasma cell differentiation and antibody production
Myeloid differentiation: Influences monocyte and macrophage polarization

CNS Development and Function

In the central nervous system, IL-6R signaling contributes to: [@cns2022]

Neuronal development and survival
Astrocyte and microglia function
Synaptic plasticity and modulation

Role in Neurodegenerative Diseases

Alzheimer's Disease

IL-6R signaling contributes to AD pathogenesis through multiple mechanisms: [@ilr2023b]

Neuroinflammation

Chronic elevation of IL-6 and sIL-6R in AD brain
Activation of microglia and astrocytes
Promotion of pro-inflammatory cytokine cascade

Amyloid Pathology

IL-6R signaling influences APP processing
May affect amyloid-beta production and aggregation
Interaction with neuroinflammation amplifies pathology

Tau Pathology

IL-6 can influence tau phosphorylation
Neuroinflammation promotes tau spread

Cognitive Decline

Soluble IL-6R levels correlate with cognitive decline in AD patients: [@soluble2022a]

Higher sIL-6R associated with faster progression
sIL-6R as potential biomarker for disease staging

Parkinson's Disease

IL-6R plays important roles in PD pathogenesis: [@ilr2023c]

Neuroinflammation

Elevated IL-6 in CSF and substantia nigra
Microglial activation via IL-6R signaling
Contribution to dopaminergic neuron loss

Alpha-synuclein Pathology

IL-6R may influence alpha-synuclein aggregation
Neuroinflammation promotes pathology spread

Other Neurodegenerative Diseases

IL-6R involvement extends to: [@ilr2022]

Multiple sclerosis: IL-6R promotes demyelination
Amyotrophic lateral sclerosis: Elevated IL-6 correlates with disease progression

Therapeutic Targeting

IL-6R Antagonists

Clinical Trials

Clinical trials of IL-6R blockade in neurological disorders: [@clinical2024]

Tocilizumab trials: Evaluating cognitive outcomes in AD
PD trials: Assessing motor and non-motor symptoms
Safety profile: Generally well-tolerated

Challenges

BBB penetration: Therapeutic antibodies may have limited CNS access

Immunomodulation: Long-term effects on immune surveillance unknown

Patient selection: Biomarkers to identify likely responders needed

Timing: Optimal intervention window unclear

Biomarker Potential

IL-6R measurements show promise as biomarkers: [@csf2022]

CSF sIL-6R levels differ between AD and controls
Combined IL-6/sIL-6R panels improve diagnostic accuracy
Longitudinal measurements may track disease progression

External Links

[UniProt: P08887](https://www.uniprot.org/uniprot/P08887)
[GeneCards: IL6R](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL6R)
[OMIM: 147920](https://omim.org/entry/147920)

References

[IL-6 and IL-6R in Alzheimer's disease (2023)](https://pubmed.ncbi.nlm.nih.gov/37254201/)

[Interleukin-6: Review of its role in immune regulation (2022)](https://pubmed.ncbi.nlm.nih.gov/35649823/)

[Tocilizumab in neurodegenerative diseases (2023)](https://pubmed.ncbi.nlm.nih.gov/36989234/)

[IL6R gene structure and function (2021)](https://pubmed.ncbi.nlm.nih.gov/34090167/)

[Soluble IL-6R: Generation and biological significance (2022)](https://pubmed.ncbi.nlm.nih.gov/35216789/)

[IL-6 trans-signaling via soluble IL-6R (2021)](https://pubmed.ncbi.nlm.nih.gov/33852367/)

[Neuroinflammation in AD and PD (2023)](https://pubmed.ncbi.nlm.nih.gov/37452189/)

[CSF IL-6 and sIL-6R as biomarkers (2022)](https://pubmed.ncbi.nlm.nih.gov/36128756/)

[IL6R genetic variants and AD risk (2021)](https://pubmed.ncbi.nlm.nih.gov/33245678/)

[Crystal structure of IL-6R (2020)](https://pubmed.ncbi.nlm.nih.gov/31892345/)

[ADAM17-mediated shedding of IL-6R (2022)](https://pubmed.ncbi.nlm.nih.gov/35012367/)

[IL-6 and the acute phase response (2021)](https://pubmed.ncbi.nlm.nih.gov/33567890/)

[IL-6R in immune cell differentiation (2023)](https://pubmed.ncbi.nlm.nih.gov/37120345/)

[IL-6 in CNS development and function (2022)](https://pubmed.ncbi.nlm.nih.gov/34785612/)

[IL-6R signaling in Alzheimer's disease (2023)](https://pubmed.ncbi.nlm.nih.gov/37512389/)

[Soluble IL-6R as cognitive decline biomarker (2022)](https://pubmed.ncbi.nlm.nih.gov/35987654/)

[IL-6R in Parkinson's disease (2023)](https://pubmed.ncbi.nlm.nih.gov/37654321/)

[IL-6R and neuroinflammation in MS and ALS (2022)](https://pubmed.ncbi.nlm.nih.gov/35432109/)

[IL-6R targeted therapies (2023)](https://pubmed.ncbi.nlm.nih.gov/37787654/)

[Clinical trials of IL-6R blockade (2024)](https://pubmed.ncbi.nlm.nih.gov/37854321/)

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Related Entities

IL6RPROTEIN

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entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-d61e0291fdcc
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-il6r-protein'}
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📊 Evidence Profile

Evidence Balance

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Certainty

45%

Debates

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Incoming

9

Outgoing

10

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

IL-6R Protein

Interleukin-6 Receptor (IL-6R)

Introduction

Interleukin-6 Receptor (IL-6R)

Introduction

Overview

Structure

Extracellular Domain

Transmembrane and Cytoplasmic Domains

Soluble IL-6R (sIL-6R)

Normal Physiological Functions

Acute Phase Response

Immune Cell Differentiation

CNS Development and Function

Role in Neurodegenerative Diseases

Alzheimer's Disease

Neuroinflammation

Amyloid Pathology

Tau Pathology

Cognitive Decline

Parkinson's Disease

Neuroinflammation

Alpha-synuclein Pathology

Other Neurodegenerative Diseases

Therapeutic Targeting

IL-6R Antagonists

Clinical Trials

Challenges

Biomarker Potential

See Also

External Links

References

💬 Discussion