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 [@il35-immunology].
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 [@neuroinflammation-nd].
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.
Molecular Function
Heterodimeric Structure
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.
Receptor Signaling
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
Immunoregulatory Functions
IL35 exerts multiple immunosuppressive effects:
Role in Neurodegenerative Diseases
Alzheimer's Disease
IL35 contributes to AD pathogenesis through neuroimmune modulation [@il35-ad]:
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