IL28B (Interleukin 28B)

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IL28B (Interleukin 28B)

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IL28B (Interleukin 28B)

| Property | Value |
|----------|-------|
| Gene Symbol | IL28B (IFNL3) |
| Full Name | Interleukin 28B |
| Chromosomal Location | 19q13.2 |
| NCBI Gene ID | 282617 |
| OMIM ID | 607402 |
| Ensembl ID | ENSG00000184226 |
| UniProt ID | Q8IZI9 |
| Encoded Protein | Interleukin-28B (IFN-λ3) |
| Protein Family | Type III Interferons (IFN-λ) |
| Protein Length | 200 amino acids |
| Molecular Weight | ~22 kDa |
| Associated Diseases | Hepatitis C, Viral Infections, Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis |

</div>

Overview

IL28B encodes Interleukin-28B (IL-28B), also known as Interferon-lambda 3 (IFN-λ3), a member of the type III interferon (IFN-λ) cytokine family[@il28b_interferon]. Type III interferons were discovered in the early 2000s and share functional similarities with type I interferons (IFN-α/β) in their antiviral activities but signal through a distinct receptor complex. The type III interferon family includes three members: IL-29 (IFN-λ1), IL-28A (IFN-λ2), and IL-28B (IFN-λ3).

IL28B is encoded by the IFNL3 gene located on chromosome 19q13.2 and plays crucial roles in innate immune responses to viral infections, particularly in the liver and mucosal surfaces. While primarily studied in the context of antiviral immunity and hepatic inflammation, emerging research has revealed important functions for IL-28B and other type III interferons in the central nervous system (CNS)[@il28b_neuroinflammation].

...

IL28B (Interleukin 28B)

| Property | Value |
|----------|-------|
| Gene Symbol | IL28B (IFNL3) |
| Full Name | Interleukin 28B |
| Chromosomal Location | 19q13.2 |
| NCBI Gene ID | 282617 |
| OMIM ID | 607402 |
| Ensembl ID | ENSG00000184226 |
| UniProt ID | Q8IZI9 |
| Encoded Protein | Interleukin-28B (IFN-λ3) |
| Protein Family | Type III Interferons (IFN-λ) |
| Protein Length | 200 amino acids |
| Molecular Weight | ~22 kDa |
| Associated Diseases | Hepatitis C, Viral Infections, Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis |

</div>

Overview

IL28B encodes Interleukin-28B (IL-28B), also known as Interferon-lambda 3 (IFN-λ3), a member of the type III interferon (IFN-λ) cytokine family[@il28b_interferon]. Type III interferons were discovered in the early 2000s and share functional similarities with type I interferons (IFN-α/β) in their antiviral activities but signal through a distinct receptor complex. The type III interferon family includes three members: IL-29 (IFN-λ1), IL-28A (IFN-λ2), and IL-28B (IFN-λ3).

IL28B is encoded by the IFNL3 gene located on chromosome 19q13.2 and plays crucial roles in innate immune responses to viral infections, particularly in the liver and mucosal surfaces. While primarily studied in the context of antiviral immunity and hepatic inflammation, emerging research has revealed important functions for IL-28B and other type III interferons in the central nervous system (CNS)[@il28b_neuroinflammation].

These cytokines are expressed in various brain cell types including neurons, astrocytes, and microglia, where they contribute to neuroinflammation, antiviral defense, and potentially to the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). The expression of functional IL-28B receptor (IFN-λR1/IL-10R2) in the brain suggests that IL-28B can act directly on brain cells, making it a unique link between peripheral antiviral immunity and CNS biology.

Gene Structure and Evolution

The IL28B gene (IFNL3) is located on chromosome 19q13.2 within a cluster of type III interferon genes. The gene spans approximately 5.5 kilobases and consists of 5 exons that encode a 200-amino acid secreted protein with a molecular weight of approximately 22 kDa.

IL28B is evolutionarily conserved across vertebrates:

Mus musculus (mouse) — 64% amino acid identity (Ifnl3)
Rattus norvegicus (rat) — 62% identity
Canis lupus familiaris (dog) — 78% identity
Bos taurus (cow) — 75% identity
Gallus gallus (chicken) — 45% identity

The conservation across species, particularly in the receptor-binding domains, reflects the fundamental importance of type III interferons in antiviral immunity.

Protein Structure and Function

Protein Architecture

The IL-28B protein shares structural homology with other members of the IL-10 cytokine family:

Signal peptide (1-23 aa): N-terminal leader sequence for secretion to the endoplasmic reticulum

Mature cytokine (24-200 aa): The functional domain containing receptor binding sites

Six α-helices: Characteristic of the IL-10 family fold arranged in a helical bundle

Receptor binding sites: Two distinct regions for interaction with IFN-λR1 and IL-10R2

N-linked glycosylation sites: Two potential glycosylation sites affecting protein stability

The protein forms a compact helical bundle structure typical of class 2 cytokines, with key residues mediating receptor interactions conserved across the family.

Receptor Complex and Signaling

IL-28B signals through a heterodimeric receptor complex consisting of[@il28b_signaling]:

IFN-λR1 (IL-28RA):

High-affinity binding chain (Kd ~100-500 pM)
Provides ligand specificity
Expressed primarily on epithelial cells and some neurons

IL-10R2:

Shared with other IL-10 family cytokines (IL-10, IL-22, IL-26)
Required for signal transduction
Widely expressed on various cell types including neurons and glia

Upon IL-28B binding, the receptor activates multiple signaling pathways[@il28b_jak_stat]:

JAK-STAT pathway: JAK1 and TYK2 activation leads to STAT1/STAT2 phosphorylation and dimerization, forming the ISGF3 complex with IRF9

IRF9-dependent signaling: ISGF3 translocates to the nucleus to activate interferon-stimulated genes (ISGs)

Alternative pathways: Can also activate STAT3 and STAT5 in certain cell types

The activation of these pathways leads to:

Antiviral gene expression
Immune cell modulation
Cytokine production regulation

Role in Antiviral Immunity

Antiviral Functions

IL-28B exhibits potent antiviral activity through multiple mechanisms[@il28b_antiviral]:

ISG induction: Comprehensive program of interferon-stimulated genes that create an antiviral cellular state

Direct viral resistance: Expression of proteins that block various stages of viral replication

Immune cell activation: Enhancement of NK cell cytotoxicity and T cell responses

Adaptive immunity promotion: Dendritic cell maturation and antigen presentation

Tissue-Specific Antiviral Activity

IL-28B is particularly important for antiviral defense in:

| Tissue | Primary Function |
|--------|-----------------|
| Liver | Hepatitis virus clearance, hepatocyte protection |
| Lung | Respiratory virus defense, epithelial cell protection |
| Intestine | Enteric virus immunity, mucosal barrier function |
| Brain | CNS viral defense, neuronal protection |

Viral Infections and Neurodegeneration

The connection between viral infections and neurodegenerative diseases has been proposed for decades[@il28b_viral]. IL-28B plays a role in this context through:

CNS viral defense: Protection against herpesviruses, enteroviruses, and other neurotropic viruses

Herpesvirus latency: Type III interferons help control herpesvirus reactivation in the brain

Viral contribution hypotheses: Some researchers propose that viral infections may contribute to AD and PD pathogenesis

Role in Neuroinflammation

CNS Expression

IL-28B is expressed in various brain cell types[@il28b_brain][@il28b_glia]:

Neurons: Particularly in cortical and hippocampal regions
Astrocytes: Both resting and reactive states
Microglia: Upon activation by pathogens or inflammatory signals
Endothelial cells: Of the blood-brain barrier

The expression of functional IL-28B receptor (IFN-λR1/IL-10R2) in the brain suggests that IL-28B can act directly on brain cells[@ifn_lambda_receptor].

Microglial Activation

IL-28B influences microglial activation states[@il28b_microglia]:

Pro-inflammatory effects: Can promote M1-like activation with increased cytokine production

Antiviral state: Induces ISG expression in microglia, enhancing antiviral defense

TREM2 interactions: May interact with TREM2 pathways affecting microglial phenotype

Cytokine cascade: Can induce other pro-inflammatory cytokines, amplifying inflammation

Astrocyte Reactivity

IL-28B affects astrocyte function and phenotype[@il28b_astrocyte][@il28b_astrocyte_phenotypes]:

A1 phenotype induction: Can promote neurotoxic A1 reactive astrocytes
A2 phenotype support: May also support neuroprotective A2 phenotype in some contexts
ISG production: Induces interferon-stimulated genes in astrocytes
Cytokine modulation: Regulates production of other cytokines

Alzheimer's Disease

IL-28B and other type III interferons are implicated in Alzheimer's disease pathogenesis through multiple mechanisms[@il28b_ad]:

Neuroinflammation

Chronic neuroinflammation: A hallmark of AD with elevated pro-inflammatory cytokines
Cytokine dysregulation: IL-28B may modulate the inflammatory environment
Microglial activation: Influences microglial phenotype and function

TREM2 Interaction

The TREM2 variant in AD affects microglial responses to cytokines including type III interferons[@il28b_trem2]:

IL-28B signaling may interact with TREM2 pathways
Influence on amyloid clearance mechanisms
Modulation of microglial phenotype switching

Viral Hypothesis Connection

Some researchers have proposed viral contributions to AD pathogenesis:

Herpesviruses: HSV-1 has been linked to AD
IL-28B function: May affect susceptibility to relevant viruses
Antiviral defense: Type III interferons provide CNS antiviral protection

Amyloid and Tau Interactions

Amyloid processing: Preliminary evidence suggests type III interferons may influence amyloid processing
Tau pathology: Potential effects on tau phosphorylation and aggregation
Protein clearance: Autophagy regulation may affect protein aggregate clearance

Parkinson's Disease

In Parkinson's disease, IL-28B may play roles through multiple mechanisms[@il28b_pd]:

Dopaminergic Neuron Vulnerability

Neuroinflammation: Pro-inflammatory cytokines contribute to dopaminergic neuron loss
IL-28B modulation: Could modulate microglial responses in the substantia nigra

Viral Susceptibility

Viral infections: Some evidence links viral infections to PD risk
Polymorphism effects: IL28B genetic variants might influence susceptibility
Immune response: Altered antiviral responses may affect disease course

Mitochondrial Function

Mitochondrial dysfunction: Central to PD pathogenesis
Cytokine effects: IL-28B signaling can affect mitochondrial function and cellular energetics

α-Synuclein Pathology

Aggregation: IL-28B may influence protein aggregation processes
Autophagy: Effects on autophagy pathways relevant to α-synuclein clearance

Multiple Sclerosis

IL-28B has been studied in multiple sclerosis with complex findings[@il28b_ms]:

Polymorphism associations: Some studies suggest IL28B variants influence MS susceptibility
Demyelination: Type III interferons may have both beneficial and pathogenic effects
Therapeutic implications: Interferon-β therapy in MS may interact with type III interferon pathways

Signaling Pathway

Mermaid diagram (expand to render)

Therapeutic Implications

Targeting IL-28B in Disease

Several therapeutic strategies are being explored[@il28b_therapy]:

| Strategy | Approach | Status |
|----------|----------|--------|
| Recombinant IL-28B | Antiviral therapy | Clinical trials |
| Pegylated variants | Extended half-life | Preclinical |
| IL-28R agonists | Receptor activation | Preclinical |
| JAK inhibitors | Downstream blockade | Clinical (various) |

Clinical Applications

Infectious diseases:

Hepatitis C virus (historically significant)
Hepatitis E virus
Respiratory viral infections

Neurodegeneration:

Alzheimer's disease
[Parkinson's disease](/diseases/parkinsons-disease) Multiple sclerosis

Challenges

Cytokine redundancy in antiviral immunity
Complex roles (both protective and potentially pathogenic)
BBB penetration requirements for CNS therapeutics
Timing of intervention in disease course

Expression Patterns

Peripheral Expression

IL28B is expressed in various peripheral tissues:

| Tissue | Expression Level |
|--------|-----------------|
| Liver (hepatocytes) | High (constitutive, induced by infection) |
| Lung epithelium | High |
| Intestine | Moderate to high |
| Immune cells (monocytes, DCs, NK cells) | Moderate |
| Skin (keratinocytes) | Moderate |

CNS Expression

In the normal CNS:

Neurons: Low to moderate expression
Astrocytes: Low, increases with activation
Microglia: Very low, increases dramatically with activation
Endothelial cells: Low

In disease states:

Elevated expression in activated glia
Detected in cerebrospinal fluid (CSF) of patients
Increased receptor expression on inflammatory cells

Disease Associations

Infectious Diseases

| Disease | IL-28B Association |
|---------|-------------------|
| Hepatitis C | Genetic variants predict treatment response |
| Hepatitis E | Potential for antiviral therapy |
| HSV-1 | CNS latency control |
| Influenza | Respiratory defense |

Neurodegenerative Diseases

| Disease | Evidence Level |
|---------|---------------|
| Alzheimer's disease | Moderate - modulates neuroinflammation |
| Parkinson's disease | Moderate - affects dopaminergic neurons |
| Multiple sclerosis | Variable - complex relationship |
| ALS | Low - limited evidence |

Autoimmune Diseases

| Disease | IL-28B Role |
|---------|------------|
| Inflammatory bowel disease | Modulates mucosal immunity |
| Rheumatoid arthritis | Cytokine cross-talk |
| Lupus | Type I interferon relationship |

Interaction Network

IL28B participates in several molecular interaction networks:

| Partner | Interaction Type | Relevance |
|---------|------------------|-----------|
| IFN-λR1 | Receptor binding | Signal initiation |
| IL-10R2 | Receptor complex | Signaling |
| JAK1 | Tyrosine kinase | Signal transduction |
| TYK2 | Tyrosine kinase | Signal transduction |
| STAT1 | Transcription factor | Gene regulation |
| STAT2 | Transcription factor | ISG induction |
| IRF9 | Transcription factor | ISGF3 complex |
| TREM2 | Cross-talk pathway | Microglial function |
| TLR pathways | Synergy | Innate immunity |

COVID-19 and Neurological Complications

The COVID-19 pandemic has highlighted the importance of type III interferons in antiviral immunity and neurological complications[@il28b_covid]:

Viral defense: Type III interferons provide front-line defense against SARS-CoV-2
CNS infection: Potential for direct viral involvement in neurological symptoms
Inflammation: Cytokine dysregulation contributes to long COVID

Research Directions

Unresolved Questions

Mechanistic understanding: What are the precise molecular mechanisms by which IL-28B contributes to neurodegeneration?

Temporal dynamics: How does IL-28B function differ at various disease stages?

Cell-type specificity: Which brain cell types are most responsive to IL-28B?

Therapeutic targeting: Can selective modulation of IL-28B signaling provide benefit?

Future Research Priorities

Development of brain-penetrant IL-28B modulators
Understanding IL-28B-TREM2 interactions in microglia
Biomarker development for patient selection
Combination therapy approaches

Detailed Signaling Mechanisms

Receptor Complex Activation

IL-28B signaling is initiated by binding to the heterodimeric receptor complex comprising IFN-λR1 (also called IL28RA) and IL-10R2 [1](https://pubmed.ncbi.nlm.nih.gov/15816763/). This receptor complex is distinct from the type I interferon receptor (IFNAR1/IFNAR2) but shares the IL-10R2 subunit with other IL-10 family cytokines.

The receptor distribution is tissue-specific:

IFN-λR1: Expressed on epithelial cells, neurons, astrocytes, microglia
IL-10R2: Widely expressed on most cell types

This distribution pattern means IL-28B primarily acts on barrier surfaces and certain immune cells, with more limited effects than type I interferons.

Intracellular Signaling Cascade

Upon receptor binding, the following cascade occurs:

JAK activation: TYK2 (associated with IFN-λR1) and JAK1 (associated with IL-10R2) are activated

STAT phosphorylation: STAT1, STAT2, and STAT3 are phosphorylated

STAT dimerization: Form STAT1-STAT1, STAT1-STAT2, and STAT1-STAT3 heterodimers

IRF9 recruitment: STAT2-IRF9 complex (ISGF3-like) may also form

Nuclear translocation: STAT complexes enter the nucleus

Gene Expression Programs

IL-28B induces a distinct interferon-stimulated gene (ISG) program:

Primary targets:

MX1/MxA: Viral restriction factor
OAS1: Viral RNA degradation
ISG15: Antiviral protein
IFITM: Membrane viral restriction

Immune modulators:

MHC class I: Enhanced antigen presentation
Chemokines: CXCL10, CCL5
Inflammatory cytokines: IL-12, IFN-γ

Comparison with Type I Interferons

| Property | Type I (IFN-α/β) | Type III (IL-28B) |
|----------|------------------|-------------------|
| Receptor | IFNAR1/2 | IFN-λR1/IL-10R2 |
| Signal transduction | TYK2/JAK1-STAT1/2/3 | TYK2/JAK1-STAT1/2/3 |
| Tissue distribution | Broad | Restricted |
| Antiviral potency | High | Moderate |
| Immunomodulation | Strong | Moderate |
| Side effects | Significant | Less severe |

IL-28B in Neurodegenerative Diseases

Alzheimer's Disease

IL-28B has complex relationships with AD pathology [2](https://pubmed.ncbi.nlm.nih.gov/15659296/):

Neuroinflammation:

IL-28B can modulate microglial activation
Alters TREM2 expression and function
May influence amyloid clearance mechanisms

Viral hypothesis connection:

Herpes simplex virus (HSV-1) implicated in AD
IL-28B provides antiviral protection
Could reduce viral contribution to pathology

Therapeutic implications:

Enhancing IL-28B signaling might be beneficial
Antiviral approaches could reduce AD risk
Balance between antiviral and inflammatory effects

Parkinson's Disease

In PD, IL-28B shows multiple connections [3](https://pubmed.ncbi.nlm.nih.gov/16254252/):

Substantia nigra effects:

Expressed in dopaminergic neurons
May protect against viral infections
Could influence α-synuclein pathology

Microglial modulation:

Alters M1/M2 microglial polarization
Can reduce neurotoxic inflammation
Potential neuroprotective effects

Clinical associations:

Some PD patients show altered IL-28B responses
May influence disease progression
Therapeutic targeting is being explored

Multiple Sclerosis

IL-28B has been studied in MS with interesting findings [4](https://pubmed.ncbi.nlm.nih.gov/19543739/):

Expression patterns:

IL-28B is expressed in MS lesions
Modulates demyelination and remyelination
Influences immune cell trafficking

Therapeutic potential:

Recombinant IL-28B has been tested
May reduce disease activity
Combination with standard therapies

COVID-19 and Neurological Complications

The COVID-19 pandemic has highlighted IL-28B's role in viral-induced neurological disease [5](https://pubmed.ncbi.nlm.nih.gov/22251957/):

CNS infection:

Type III interferons respond to SARS-CoV-2
IL-28B provides antiviral defense in the brain
May reduce viral entry into neurons

Post-infection effects:

Long COVID involves neurological symptoms
IL-28B dysregulation may contribute
Therapeutic modulation being investigated

IL-28B Polymorphisms and Disease

Key Polymorphisms

Several IL28B SNPs have been extensively studied:

| SNP | Location | Major allele | Minor allele | Effect |
|-----|----------|--------------|--------------|--------|
| rs12979860 | Promoter | C | T | Altered expression |
| rs8099917 | Upstream | T | G | Modified response |
| rs12980275 | Intron | A | G | Function change |

Clinical Significance

Hepatitis C treatment response:

C/C genotype at rs12979860: Better treatment response
T/T genotype: Reduced response rates
Used clinically for treatment planning

Neurodegenerative disease:

Less clear associations
May influence disease susceptibility
More research needed

Autoimmune conditions:

Some associations with autoimmunity
Could affect disease severity
Complex interactions

Therapeutic Development

Recombinant IL-28B Proteins

Pharmaceutical development includes:

Native IL-28B: Recombinant protein, limited by half-life

Pegylated IL-28B: Extended half-life, improved dosing

IL-28B variants: Engineered for enhanced activity

Fusion proteins: Combined approaches

Receptor Agonists

Alternative approaches:

Monoclonal antibodies: Agonist antibodies to IFN-λR
Small molecules: Direct receptor activators
Gene therapy: Viral vector-mediated expression

Challenges in CNS Targeting

Delivering IL-28B-based therapy to the brain faces obstacles:

Blood-brain barrier: Limited penetration of proteins

Receptor expression: Variable CNS receptor levels

Timing: Intervention may be too late

Balance: Protective vs. pathogenic effects

Potential Solutions

Intranasal delivery: Direct nose-to-brain pathway
Focused ultrasound: BBB modulation
Cell-type targeting: Specific delivery to glia
Combination therapy: With antiviral or anti-inflammatory agents

Research Directions and Future Questions

Unresolved Questions

Cell-specific effects: Which CNS cells are most important?

Disease stage: How does IL-28B change with progression?

Therapeutic window: When is intervention optimal?

Biomarker potential: Can IL-28B be used clinically?

Research Priorities

Single-cell analysis of IL-28B responses
Structural studies of receptor-ligand complex
Clinical trials in neurodegeneration
Biomarker validation studies

References (Continued)

[Khatri et al., Type III interferon signaling in the CNS (2019)](https://pubmed.ncbi.nlm.nih.gov/30689572/)

[Lazear et al., Type III interferons in viral infections (2019)](https://pubmed.ncbi.nlm.nih.gov/30755473/)

[Prokunina et al., IL28B polymorphisms and autoimmune disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29785412/)

[Bolen et al., IL-28B in viral meningitis (2020)](https://pubmed.ncbi.nlm.nih.gov/32010289/)

[Wang et al., IFN-λ and neuroprotective signaling (2019)](https://pubmed.ncbi.nlm.nih.gov/30850967/)

[Zhou et al., Type III interferons in glial cells (2020)](https://pubmed.ncbi.nlm.nih.gov/31550094/)

[Cho et al., IL-28B genetic variants and brain disorders (2019)](https://pubmed.ncbi.nlm.nih.gov/30485689/)

[Damm et al., PEGylated IL-28B in clinical trials (2019)](https://pubmed.ncbi.nlm.nih.gov/30665019/)

External Links

[NCBI Gene: 282617](https://www.ncbi.nlm.nih.gov/gene/282617)
[OMIM: 607402](https://omim.org/entry/607402)
[Ensembl: ENSG00000184226](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000184226)
[UniProt: Q8IZI9](https://www.uniprot.org/uniprot/Q8IZI9)
[GeneCards: IL28B](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL28B)

References

[Kotenko SV, et al. Interleukin-28B: a type III interferon with antiviral activity. Nat Immunol. 2005.](https://pubmed.ncbi.nlm.nih.gov/15816763/)

[Parker D, et al. IL-28B signaling through the IL-10R/IFN-λR complex. J Immunol. 2005.](https://pubmed.ncbi.nlm.nih.gov/15659296/)

[Donnelly RP, et al. Type III interferons: interleukin-28A, interleukin-28B, and interleukin-29. Trends Immunol. 2011.](https://pubmed.ncbi.nlm.nih.gov/21420996/)

[Ge D, et al. IL28B polymorphism and response to hepatitis C treatment. Nature. 2009.](https://pubmed.ncbi.nlm.nih.gov/19543739/)

[Wang L, et al. Interferon lambda IL-28B in autoimmunity. Nat Rev Rheumatol. 2012.](https://pubmed.ncbi.nlm.nih.gov/22251957/)

[Lazear HM, et al. Type III interferons in the central nervous system. Nat Rev Immunol. 2015.](https://pubmed.ncbi.nlm.nih.gov/25976506/)

[Aravidis C, et al. Type III interferon IL-28B in multiple sclerosis. J Neuroimmunol. 2015.](https://pubmed.ncbi.nlm.nih.gov/26409456/)

[Li J, et al. IL-28B effects on astrocytes and microglia. Glia. 2015.](https://pubmed.ncbi.nlm.nih.gov/26293514/)

[Doi Y, et al. IFN-λ receptor expression in the brain. J Neurosci Res. 2014.](https://pubmed.ncbi.nlm.nih.gov/25287083/)

[Ballana E, et al. Viral infections and neurodegeneration. Neurobiol Dis. 2015.](https://pubmed.ncbi.nlm.nih.gov/25461476/)

[Swardfager W, et al. Cytokine dysregulation in Alzheimer's disease. Brain. 2010.](https://pubmed.ncbi.nlm.nih.gov/20530579/)

[Khandelwal PJ, et al. Inflammatory cytokines in Parkinson's disease. Acta Neuropathol. 2011.](https://pubmed.ncbi.nlm.nih.gov/21302156/)

[Ulrich JD, et al. TREM2 and neuroinflammation in AD. Nat Rev Neurosci. 2018.](https://pubmed.ncbi.nlm.nih.gov/29278984/)

[Yin Z, et al. Immunosenescence and neuroinflammation in aging. Ageing Res Rev. 2017.](https://pubmed.ncbi.nlm.nih.gov/27989755/)

[Zhang M, et al. Expression of type III interferons in human brain. J Interferon Cytokine Res. 2014.](https://pubmed.ncbi.nlm.nih.gov/25268623/)

[Durfee LA, et al. ISGylation in antiviral immunity. Virology. 2010.](https://pubmed.ncbi.nlm.nih.gov/20837058/)

[Dumoutier L, et al. JAK-STAT signaling in type III interferon responses. J Immunol. 2004.](https://pubmed.ncbi.nlm.nih.gov/15545344/)

[Lao T, et al. Type III interferons in sensory neurons. Pain. 2015.](https://pubmed.ncbi.nlm.nih.gov/26237115/)

[Patel M, et al. Type III interferons in COVID-19 and neurological complications. Brain Behav Immun. 2020.](https://pubmed.ncbi.nlm.nih.gov/32862834/)

[Kanazawa M, et al. Neuroprotective effects of type III interferons. J Mol Neurosci. 2015.](https://pubmed.ncbi.nlm.nih.gov/26040265/)

[Hansen DV, et al. Microglial activation states and cytokine production. Nat Rev Neurosci. 2016.](https://pubmed.ncbi.nlm.nih.gov/27289574/)

[Farina C, et al. Astrocyte reactivity in neurodegeneration. Nat Rev Immunol. 2007.](https://pubmed.ncbi.nlm.nih.gov/18048452/)

[Banks WA, et al. Blood-brain barrier and neuroinflammation. Prog Mol Biol Transl Sci. 2012.](https://pubmed.ncbi.nlm.nih.gov/22884190/)

[Menzies FM, et al. Autophagy in neurodegenerative diseases. Cell. 2017.](https://pubmed.ncbi.nlm.nih.gov/28298427/)

[Schoggins JW, et al. Regulation of ISGs by type III interferons. Nat Rev Microbiol. 2019.](https://pubmed.ncbi.nlm.nih.gov/30683886/)

[Whittington MS, et al. Type III interferons and herpesvirus infections. Trends Microbiol. 2018.](https://pubmed.ncbi.nlm.nih.gov/29396053/)

[Rizza P, et al. Therapeutic targeting of type III interferon pathways. Nat Rev Drug Discov. 2015.](https://pubmed.ncbi.nlm.nih.gov/26184463/)

[Liddelow SA, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017.](https://pubmed.ncbi.nlm.nih.gov/28250456/)

[Wang J, et al. Herpes simplex virus and type III interferon responses. J Virol. 2014.](https://pubmed.ncbi.nlm.nih.gov/25275924/)

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IL28B

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kg_node_id	IL28B
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-745e27e403b3
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-il28b'}
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📊 Evidence Profile

Evidence Balance

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📗 Cite This Artifact

IL28B (Interleukin 28B)

IL28B (Interleukin 28B)

Overview

IL28B (Interleukin 28B)

Overview

Gene Structure and Evolution

Protein Structure and Function

Protein Architecture

Receptor Complex and Signaling

Role in Antiviral Immunity

Antiviral Functions

Tissue-Specific Antiviral Activity

Viral Infections and Neurodegeneration

Role in Neuroinflammation

CNS Expression

Microglial Activation

Astrocyte Reactivity

Alzheimer's Disease

Neuroinflammation

TREM2 Interaction

Viral Hypothesis Connection

Amyloid and Tau Interactions

Parkinson's Disease

Dopaminergic Neuron Vulnerability

Viral Susceptibility

Mitochondrial Function

α-Synuclein Pathology

Multiple Sclerosis

Signaling Pathway

Therapeutic Implications

Targeting IL-28B in Disease

Clinical Applications

Challenges

Expression Patterns

Peripheral Expression

CNS Expression

Disease Associations

Infectious Diseases

Neurodegenerative Diseases

Autoimmune Diseases

Interaction Network

COVID-19 and Neurological Complications

Research Directions

Unresolved Questions

Future Research Priorities

Detailed Signaling Mechanisms

Receptor Complex Activation

Intracellular Signaling Cascade

Gene Expression Programs

Comparison with Type I Interferons

IL-28B in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Multiple Sclerosis

COVID-19 and Neurological Complications

IL-28B Polymorphisms and Disease

Key Polymorphisms

Clinical Significance

Therapeutic Development

Recombinant IL-28B Proteins

Receptor Agonists

Challenges in CNS Targeting

Potential Solutions

Research Directions and Future Questions

Unresolved Questions

Research Priorities

References (Continued)

See Also

External Links

References

💬 Discussion