| Attribute |
Value |
Sources |
| Symbol |
IL35 |
|
| Name |
Interleukin 35 |
|
| Chromosome |
5q33.1 |
|
| NCBI Gene ID |
359948 |
|
| UniProt ID |
Q8IWU6 |
|
| Gene Type |
Protein coding (heterodimeric cytokine) |
|
IL35 is a member of the interleukin-12 (IL-12) family of cytokines, distinguished by its unique heterodimeric structure composed of IL-12A (p35) and IL27RB (EBI3) subunits. As one of the most immunosuppressive cytokines in the IL-12 family, IL35 plays crucial roles in regulating immune responses, particularly through its actions on regulatory T cells (Tregs) and effector T cells .
In the context of neurodegenerative diseases, IL35's immunomodulatory functions are highly relevant. Both Alzheimer's disease (AD) and Parkinson's disease (PD) feature chronic neuroinflammation driven by microglial activation and peripheral immune cell infiltration. IL35's ability to suppress inflammatory responses positions it as a potential therapeutic target for modulating the neuroimmune axis in these conditions .
Unlike other IL-12 family members that promote inflammatory Th1 or Th17 responses, IL35 primarily exerts anti-inflammatory effects. This unique profile makes IL35 an attractive candidate for therapeutic intervention in diseases where excessive inflammation contributes to neuronal damage.
IL35 is composed of two subunits:
- IL12A (p35): Shared with IL-12 and IL-35
- IL27RB (EBI3): Shared with IL-27
This structure enables IL35 to signal through multiple receptor combinations.
IL35 signals through two receptor complexes:
1. IL12Rβ1/IL12Rβ2 (classical IL-12 receptor)
- Activates STAT4 signaling
- Promotes Th1 responses
2. IL27RA/IL12Rβ2 (IL-27 receptor)
- Activates STAT1 and STAT3
- Promotes regulatory functions
3. GP130 (alternative receptor)
- Mediates immunosuppressive signaling
- Activates STAT3 predominantly
IL35 exerts multiple immunosuppressive effects:
| Function |
Mechanism |
Outcome |
| Treg expansion |
STAT3 activation |
Increased immunosuppression |
| Effector T cell inhibition |
Suppressed proliferation |
Reduced autoimmunity |
| Cytokine production |
Inhibited inflammatory cytokines |
Anti-inflammatory state |
| Proliferation block |
Cell cycle arrest |
Controlled immune response |
IL35 contributes to AD pathogenesis through neuroimmune modulation :
1. Chronic Neuroinflammation
- AD brains show persistent microglial activation
- IL35 levels are dysregulated in AD
- Restoring IL35 signaling may reduce inflammation
2. Regulatory T Cell Dysfunction
- Tregs are reduced or dysfunctional in AD
- IL35 promotes Treg expansion and function
- Enhancing IL35 could restore immune regulation
3. Amyloid Clearance
- IL35 modulates microglial phagocytosis
- May affect amyloid-β clearance efficiency
- Therapeutic potential for immunotherapy
4. Tau Pathology
- Neuroinflammation drives tau pathology
- IL35-mediated inflammation reduction may slow progression
- Indirect effects on tau phosphorylation
IL35 contributes to PD through :
1. Dopaminergic Neuron Protection
- Neuroinflammation drives dopaminergic loss
- IL35 can suppress microglial activation
- Protects vulnerable neurons
2. Peripheral Immune Dysregulation
- PD involves peripheral immune abnormalities
- Tregs are reduced in PD patients
- IL35 could restore Treg function
3. Neuroinflammation in Substantia Nigra
- Microglial activation is prominent
- IL35 reduces inflammatory cytokine production
- May slow progression
4. Alpha-Synuclein Inflammation
- α-Synuclein triggers neuroinflammation
- IL35 modulation may reduce pathology spread
IL35-based therapeutic approaches:
- IL35 protein therapy: Administer recombinant IL35
- Gene therapy: Express IL35 in target tissues
- Small molecule agonists: Activate IL35 signaling
- Treg enhancement: Expand Tregs via IL35
- Anti-inflammatory strategies: Reduce chronic neuroinflammation
IL35 expression in the brain:
- Microglia: Primary source in CNS
- Neurons: Low level expression
- Astrocytes: Some expression
- Infiltrating immune cells: T cells, macrophages
Peripheral expression:
- Regulatory T cells (highest)
- Dendritic cells
- B cells (some subsets)
- IL12Rβ1 (IL12RB1)
- IL12Rβ2 (IL12RB2)
- IL27RA (IL27RA)
- GP130 (IL6ST)
- STAT3
- STAT4
- STAT1
- JAK2, JAK4
- Regulatory T cells (Tregs)
- Effector T cells
- B cells
- Dendritic cells
- Macrophages
- Aβ (amyloid-beta)
- Tau
- Alpha-synuclein
flowchart TD
subgraph IL35_Function
A["IL35 Gene"] --> B["IL35 Protein"]
B --> C["Immunosuppressive<br/>Cytokine"]
C --> D["Treg Expansion"]
C --> E["Effector T Cell<br/>Inhibition"]
end
subgraph Normal_Immune
D --> F["Immune<br/>Regulation"]
E --> F
F --> G["Balanced<br/>Response"]
end
subgraph AD_Pathology
H["Alzheimer's<br/>Disease"] --> I["Neuroinflammation"]
I --> J["Microglial<br/>Activation"]
J --> K["Neuronal<br/>Damage"]
L["Treg<br/>Dysfunction"] --> I
end
subgraph PD_Pathology
M["Parkinson's<br/>Disease"] --> N["Dopaminergic<br/>Inflammation"]
N --> O["Neuronal<br/>Loss"]
P["Treg<br/>Reduction"] --> N
end
subgraph Therapeutic
Q["IL35 Therapy"] --> R["Treg<br/>Restoration"]
R --> S["Inflammation<br/>Reduction"]
S --> T["Neuroprotection"]
end
style A fill:#e3f2fd
style H fill:#ffcdd2
style M fill:#ffcdd2
style T fill:#4caf50
- IL12A — IL35 subunit (p35)
- IL27RB — IL35 subunit (EBI3)
- IL27 — Related immunosuppressive cytokine