IL6 Signal Transducer (gp130) is encoded by the IL6ST gene on chromosome 5q11.2. It is the common signal transducing receptor subunit for the interleukin-6 (IL-6) family of cytokines, including IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), and ciliary neurotrophic factor (CNTF). gp130 is a critical mediator of neuroinflammation and neurotrophic signaling in the central nervous system.
- Length: 917 amino acids
- Molecular Weight: ~130 kDa (glycosylated)
- Domains:
- Extracellular domain (1-597): Six fibronectin type-III repeats
- Transmembrane domain (598-620): Single-pass membrane helix
- Cytoplasmic domain (621-917): Janus kinase (JAK) binding and STAT3 docking
| Motif |
Position |
Function |
| Box1 |
620-635 |
JAK binding, signal initiation |
| Box2 |
636-655 |
STAT3 recruitment |
| YXXQ motifs |
Multiple |
STAT3 docking sites |
| SHP2 binding |
Y759 |
MAPK pathway activation |
- Coreceptor for IL-6 family cytokines
- Activates JAK1/TYK2 kinases upon ligand binding
- Dual signaling via STAT3 and MAPK/ERK pathways
- Regulates acute phase response and immune cell differentiation
- CNTF signaling: Essential for motor neuron survival
- LIF signaling: Supports neural stem cell maintenance
- IL-6 signaling: Mediates neuroinflammation responses
- Regulates synaptic plasticity and memory formation
-
Neuroinflammation
- IL-6/gp130 promotes microglial activation
- Chronic signaling contributes to chronic neuroinflammation
- STAT3 activation in reactive astrocytes
-
Amyloid-beta Interactions
- IL-6 signaling increases BACE1 expression
- Aβ stimulates IL-6 production in astrocytes
- Creates feed-forward inflammatory loop
-
Neuronal Survival
- CNTF/gp130 signaling provides neuroprotection
- Age-related gp130 signaling decline
- Therapeutic potential of enhancing gp130 signaling
- Elevated IL-6 in PD patients and CSF
- gp130 in dopaminergic neuron survival
- Involvement in microglial activation in substantia nigra
- CNTF/gp130 pathway dysfunction in motor neurons
- Therapeutic trials of CNTF in ALS (failed due to side effects)
- Altered gp130 signaling in astrocytes
| Agent |
Status |
Mechanism |
| IL-6 |
Experimental |
Direct ligand activation |
| CNTF |
Clinical trials |
Neurotrophic via gp130 |
| Hyper-IL-6 |
Preclinical |
IL-6/IL-6R fusion protein |
| Agent |
Status |
Mechanism |
| Tocilizumab |
Approved (RA) |
IL-6R blocking antibody |
| Sarilumab |
Approved |
IL-6R blocking antibody |
| sgp130Fc |
Preclinical |
Soluble gp130, selective inhibition |