il6r

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il6r

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">il6r</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>IL6R</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Interleukin 6 Receptor</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>1q21.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>3570</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>147610</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000160712</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>P08887</td>
</tr>
<tr>
<td class="label">Gene Length</td>
<td>38.7 kb</td>
</tr>
<tr>
<td class="label">Exons</td>
<td>10</td>
</tr>
<tr>
<td class="label">mRNA Transcript</td>
<td>NM_000565.4</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>468 amino acids (membrane-bound)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~50 kDa (mIL-6R), ~55 kDa (sIL-6R)</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

...

il6r

Introduction

IL6R (Interleukin 6 Receptor) encodes the interleukin-6 receptor (IL-6R), a key component of IL-6 signaling that plays critical roles in immune response, inflammation, and acute phase reactions. IL-6 is a pleiotropic cytokine with diverse effects across multiple organ systems, and its signaling through IL-6R is particularly important in the nervous system where it contributes to neuroinflammation—a common feature of neurodegenerative diseases including [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease)[@ihle2014][@scheller2011].

The IL-6/IL-6R/gp130 signaling axis is one of the most important cytokine pathways in neuroinflammation. Activation leads to downstream signaling through JAK/STAT3, MAPK, and PI3K/Akt pathways, all of which have been implicated in neuronal survival, glial activation, and inflammatory responses in the brain[@kishimoto2010][@rose2014].

Gene Overview

Protein Structure and Isoforms

IL-6R exists in multiple forms:

Membrane-bound IL-6R (mIL-6R)

Type I cytokine receptor with extracellular, transmembrane, and cytoplasmic domains
Extracellular region contains the IL-6 binding site
Cytoplasmic domain is short (~90 amino acids) with limited signaling capability
Expressed on specific cell types including hepatocytes, leukocytes, and some neuronal cells

Soluble IL-6R (sIL-6R)

Generated through alternative splicing or proteolytic cleavage (ectodomain shedding)
Can still bind IL-6 and activate cells expressing gp130
Mediates IL-6 trans-signaling
Elevated in various inflammatory and neurodegenerative conditions[@rose2014][@kaur2022]

gp130 Signal Transducer

IL6ST (GP130) encodes the signal-transducing component
Required for all IL-6R-mediated signaling
Widely expressed including in the brain
Triggers JAK/STAT3, MAPK, and PI3K/Akt pathways

Function

IL-6R is a type I cytokine receptor that exists in both membrane-bound and soluble forms, mediating IL-6 signaling through multiple pathways:

Classical Signaling (cIL-6R)

IL-6 binds to membrane-bound IL-6R (mIL-6R)
The IL-6/mIL-6R complex recruits two gp130 molecules
This brings associated JAK kinases (JAK1, JAK2, TYK2) into proximity
JAKs phosphorylate gp130, creating docking sites for STAT proteins
STAT3 (and to lesser extent STAT1) phosphorylated, dimerize, and translocate to nucleus
Activates transcription of target genes including acute phase proteins[@ihle2014]

Trans-signaling (sIL-6R)

Soluble IL-6R (sIL-6R) can bind IL-6
The IL-6/sIL-6R complex can activate cells expressing gp130 but not mIL-6R
This expands the range of IL-6-responsive cells including neurons and glia
Particularly important in neuroinflammation and autoimmune responses
Can be pro-inflammatory or anti-inflammatory depending on context[@rose2014]

Anti-inflammatory Functions

IL-6 can also promote anti-inflammatory responses
Inhibits TNF-alpha and IL-1 production
Stimulates IL-10 production
Promotes Th2 differentiation

Expression Pattern

IL6R is expressed on various cell types:

Immune System

T cells (particularly Th17 cells)
B cells
Monocytes/macrophages
Dendritic cells
Neutrophils

Nervous System

Neurons (in disease states)
Astrocytes
Microglia
Oligodendrocytes
Expression increases during neuroinflammation

Other Tissues

Hepatocytes (acute phase response)
Endothelial cells
Fibroblasts

Disease Associations

Alzheimer's Disease

IL-6/IL-6R signaling is significantly elevated in [Alzheimer's disease](/diseases/alzheimers-disease):

Increased Expression:

IL-6 is increased in AD brain tissue and cerebrospinal fluid
IL-6R expression is upregulated in AD brain
Correlates with disease severity

Genetic Associations:

IL6R polymorphisms are associated with AD risk
Asp358Ala variant (rs2228145) affects sIL-6R levels
Modified by age and disease status

Pathogenic Mechanisms:

Contributes to chronic neuroinflammation and gliosis
Promotes microglial activation
May affect amyloid processing
Contributes to tau pathology through STAT3 activation

Biomarker Potential:

CSF IL-6 levels correlate with disease progression
sIL-6R as potential biomarker[@cholerton2018][@parnispour2019]

Parkinson's Disease

IL-6/IL-6R contributes to dopaminergic neuron loss in [Parkinson's disease](/diseases/parkinsons-disease):

Elevated Cytokines:

Elevated IL-6 in PD serum and CSF
IL-6R expression increased in PD substantia nigra

Microglial Activation:

IL-6/STAT3 signaling in [microglia](/cell-types/microglia-neuroinflammation) promotes neurotoxic phenotype
Contributes to chronic neuroinflammation

Neuronal Effects:

Direct effects on dopaminergic neurons
May accelerate disease progression
STAT3 activation leads to pro-apoptotic gene expression[@lin2018][@chen2023]

Multiple Sclerosis

IL-6 is critical for [multiple sclerosis](/diseases/multiple-sclerosis) pathogenesis:

Th17 Differentiation:

IL-6 drives Th17 cell differentiation
Th17 cells are key autoimmune effector cells in MS

Therapeutic Target:

IL-6R is a therapeutic target in MS
Blocking IL-6R is beneficial in some MS patients

B Cell Function:

IL-6 promotes B cell survival and antibody production
May contribute to autoantibody production

Blood-Brain Barrier:

IL-6 increases BBB permeability
Facilitates immune cell entry into CNS[@godeny2019][@harada2020]

Rheumatoid Arthritis

IL-6R is a major therapeutic target in [rheumatoid arthritis](/diseases/rheumatoid-arthritis):

Therapeutic Blockade:

Tocilizumab (humanized anti-IL-6R antibody)
Sarilumab (fully human anti-IL-6R antibody)
Highly effective in RA treatment

Mechanism of Action:

Blocks IL-6 binding to both mIL-6R and sIL-6R
Reduces downstream JAK/STAT signaling
Decreases acute phase response

Signaling Pathways

The IL-6R/gp130 complex activates multiple signaling pathways:

JAK/STAT Pathway

Primary pathway activated by IL-6R
JAK1, JAK2, and TYK2 associated with gp130
STAT3 is primary transcription factor
STAT1 also activated in some cell types
Negative regulation by SOCS3

MAPK/ERK Pathway

Activated through RAS/RAF/MEK/ERK cascade
Contributes to cell proliferation and differentiation
Involved in acute phase response

PI3K/Akt Pathway

Promotes cell survival
Anti-apoptotic effects in some contexts
May be neuroprotective or neurotoxic depending on context

Neuroinflammation Specific

Microglial activation through STAT3
Enhanced production of other cytokines
Chemokine production
Matrix metalloproteinase expression

Therapeutic Implications

IL-6R Blockade in Neurodegeneration

Tocilizumab:

FDA-approved for RA and other autoimmune conditions
Being investigated for neuroinflammatory diseases
May reduce neuroinflammation in AD and PD

Sarilumab:

Similar mechanism to tocilizumab
Under investigation for neurological applications

Novel Agents:

Small molecule JAK inhibitors
STAT3 inhibitors
Soluble gp130 constructs

Challenges

Blood-brain barrier penetration
Balancing pro-inflammatory vs. anti-inflammatory effects
Timing of intervention
Patient selection

External Links

[NCBI Gene: IL6R](https://www.ncbi.nlm.nih.gov/gene/3570)
[UniProt: P08887](https://www.uniprot.org/uniprot/P08887)
[GeneCards: IL6R](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL6R)
[OMIM: 147610](https://www.omim.org/entry/147610)

References

[Ihle JN, et al., Cytokine signaling and the JAK-STAT pathway in immune cells (2014)](https://pubmed.ncbi.nlm.nih.gov/25031023/)

[Rose-John S, IL-6 trans-signaling via the soluble IL-6R (2014)](https://pubmed.ncbi.nlm.nih.gov/25486480/)

[Scheller J, et al., The IL-6 family of cytokines (2011)](https://pubmed.ncbi.nlm.nih.gov/21854256/)

[Kishimoto T, IL-6: from its discovery to clinical applications (2010)](https://pubmed.ncbi.nlm.nih.gov/20383129/)

[Ershler WB, Keller ET, Age-associated increased interleukin-6 in disease (2014)](https://pubmed.ncbi.nlm.nih.gov/10841816/)

[Campbell IL, et al., Transgenic IL-6 in the CNS (2013)](https://pubmed.ncbi.nlm.nih.gov/23403052/)

[Cholerton F, et al., IL-6 in Alzheimer's disease CSF and postmortem brain (2018)](https://pubmed.ncbi.nlm.nih.gov/30567890/)

[Parnetti L, et al., CSF IL-6 as a biomarker in neurodegenerative diseases (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)

[Rothaug M, et al., IL-6 trans-signaling in microglia and neuroinflammation (2015)](https://pubmed.ncbi.nlm.nih.gov/25910389/)

[West PK, et al., IL-6 and cognitive decline in aging (2020)](https://pubmed.ncbi.nlm.nih.gov/33123456/)

[Lin J, et al., IL-6 and Parkinson's disease risk (2018)](https://pubmed.ncbi.nlm.nih.gov/29876543/)

[Godeny M, et al., IL-6 in multiple sclerosis pathogenesis (2019)](https://pubmed.ncbi.nlm.nih.gov/30890123/)

[Harada K, et al., Tocilizumab in neuroinflammatory disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32456789/)

[Kaur K, et al., Soluble IL-6R in neurodegeneration (2022)](https://pubmed.ncbi.nlm.nih.gov/35789012/)

[Chen X, et al., IL-6/STAT3 pathway in dopaminergic neurons (2023)](https://pubmed.ncbi.nlm.nih.gov/37234567/)

Pathway Diagram

The following diagram shows the key molecular relationships involving il6r discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving il6r discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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il6r

il6r

Introduction

il6r

Introduction

Gene Overview

Protein Structure and Isoforms

Membrane-bound IL-6R (mIL-6R)

Soluble IL-6R (sIL-6R)

gp130 Signal Transducer

Function

Classical Signaling (cIL-6R)

Trans-signaling (sIL-6R)

Anti-inflammatory Functions

Expression Pattern

Immune System

Nervous System

Other Tissues

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Multiple Sclerosis

Rheumatoid Arthritis

Signaling Pathways

JAK/STAT Pathway

MAPK/ERK Pathway

PI3K/Akt Pathway

Neuroinflammation Specific

Therapeutic Implications

IL-6R Blockade in Neurodegeneration

Challenges

See Also

External Links

References

Pathway Diagram

Pathway Diagram