IL28A (Interleukin-28A)

IL28A (Interleukin-28A)

<div class="infobox infobox-gene">

| Property | Value |
|----------|-------|
| Gene Symbol | IL28A |
| Full Name | Interleukin 28A |
| Chromosomal Location | 19q13.2 |
| NCBI Gene ID | 282616 |
| OMIM ID | 607401 |
| Ensembl ID | ENSG00000183709 |
| UniProt ID | Q8IZJ0 |
| Encoded Protein | Interleukin-28A (IL-28A) |
| Protein Family | Type III Interferons (IFN-λ) |
| Gene Length | ~7.5 kb |
| Exons | 5 |
| Associated Diseases | Viral infections, Neuroinflammation |

</div>

Overview

IL28A encodes Interleukin-28A (IL-28A), also known as IFN-λ2, a member of the Type III interferon family within the larger cytokine superfamily. Type III interferons (IFN-λ1/IL-29, IFN-λ2/IL-28A, IFN-λ3/IL-28B, and IFN-λ4/IL-26) represent a more recently discovered interferon system that shares functional similarities with Type I interferons (IFN-α/β) but signals through a distinct receptor complex[@kotenko2002].

The Type III interferon system was first described in 2002 when Kotenko et al. identified IL-28R1 as the receptor for IL-28A and IL-28B, demonstrating that these cytokines signal through a unique pathway distinct from the classical Type I interferon receptors[@kotenko2002]. This discovery expanded our understanding of the interferon family and revealed additional layers of immune regulation that were previously unrecognized.

IL28A (Interleukin-28A)

<div class="infobox infobox-gene">

| Property | Value |
|----------|-------|
| Gene Symbol | IL28A |
| Full Name | Interleukin 28A |
| Chromosomal Location | 19q13.2 |
| NCBI Gene ID | 282616 |
| OMIM ID | 607401 |
| Ensembl ID | ENSG00000183709 |
| UniProt ID | Q8IZJ0 |
| Encoded Protein | Interleukin-28A (IL-28A) |
| Protein Family | Type III Interferons (IFN-λ) |
| Gene Length | ~7.5 kb |
| Exons | 5 |
| Associated Diseases | Viral infections, Neuroinflammation |

</div>

Overview

IL28A encodes Interleukin-28A (IL-28A), also known as IFN-λ2, a member of the Type III interferon family within the larger cytokine superfamily. Type III interferons (IFN-λ1/IL-29, IFN-λ2/IL-28A, IFN-λ3/IL-28B, and IFN-λ4/IL-26) represent a more recently discovered interferon system that shares functional similarities with Type I interferons (IFN-α/β) but signals through a distinct receptor complex[@kotenko2002].

The Type III interferon system was first described in 2002 when Kotenko et al. identified IL-28R1 as the receptor for IL-28A and IL-28B, demonstrating that these cytokines signal through a unique pathway distinct from the classical Type I interferon receptors[@kotenko2002]. This discovery expanded our understanding of the interferon family and revealed additional layers of immune regulation that were previously unrecognized.

IL28A is expressed primarily in epithelial tissues and immune cells, where it plays critical roles in antiviral defense and immune modulation. Recently, research has revealed that IL28A and its receptor are also expressed in the central nervous system (CNS), where they participate in neuroinflammatory and neuroprotective processes relevant to neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD)[@davies2018].

Gene Structure and Evolution

The IL28A gene is located on chromosome 19q13.2, within a genomic cluster that includes related Type III interferon genes (IL28B/IFNL3 and IL29/IFNL1). The gene spans approximately 7.5 kilobases and consists of 5 exons that encode a 200-amino acid secreted protein with a molecular weight of approximately 22 kDa.

Phylogenetically, Type III interferons are evolutionarily ancient, with orthologs identified in birds, reptiles, and fish, though they are absent in rodents. This species-specific distribution has historically complicated preclinical research on IL-28 signaling in mouse models. The evolutionary conservation across non-mammalian vertebrates suggests that Type III interferons represent an ancient antiviral defense mechanism that predates the emergence of mammals.

The genomic organization of the IFNL gene cluster shows significant haplotype variation across human populations. Single nucleotide polymorphisms (SNPs) in the IFNL3/IL28B region are strongly associated with treatment response in hepatitis C virus (HCV) infection, demonstrating the clinical importance of genetic variation in this cytokine system.

Protein Structure and Biochemistry

The IL-28A protein is synthesized as a precursor polypeptide that undergoes signal peptide cleavage to produce the mature secreted cytokine. Like other Type III interferons, IL-28A contains a characteristic helical cytokine bundle structure consisting of six α-helices arranged in an up-up-down-down topology, connected by flexible loop regions.

The IL-28A protein interacts with a heterodimeric receptor complex consisting of:

• IL28R1 (IFN-λR1): The ligand-binding chain, expressed primarily on epithelial cells and some immune cell populations
• IL10RB (IL-10 receptor subunit β): The signal-transducing chain, shared with IL-10, IL-22, and IL-26 receptors

This signaling pathway shares significant overlap with Type I interferon signaling, though Type III interferons exhibit more restricted tissue distribution due to the limited expression of IL28R1.

Receptor Distribution in the Central Nervous System

A critical finding in recent years is the expression of Type III interferon receptors in the brain. IL28R1 is expressed on various CNS cell types including:

• Neurons: Particularly in cortical and hippocampal regions
• Astrocytes: The most abundant glial cell type in the CNS
• Microglia: The brain's resident immune cells
• Oligodendrocytes: Myelin-producing cells

Research by Hermant et al. (2017) demonstrated that human astrocytes produce Type III interferons in response to viral infection, establishing an autocrine signaling loop within the CNS[@hermant2017]. This finding has significant implications for understanding how the brain responds to viral pathogens and how chronic viral infections might contribute to neurodegeneration.

Role in Neuroinflammation

Microglial Activation and Polarization

IL-28A signaling influences microglial activation, the central immune effector cells in the brain. Microglia exist on a spectrum between pro-inflammatory (M1-like) and anti-inflammatory (M2-like) activation states. Type III interferon signaling appears to favor a more regulatory microglial phenotype that may be beneficial in the context of neurodegenerative diseases.

In vitro studies demonstrate that IL-28A treatment of microglial cultures reduces the production of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 while simultaneously enhancing the expression of anti-inflammatory markers such as Arg1 and CD206. This modulation suggests that IL-28A could help resolve chronic neuroinflammation that characterizes neurodegenerative conditions.

Neuroinflammation in Alzheimer's Disease

Alzheimer's disease is characterized by chronic neuroinflammation surrounding amyloid-beta (Aβ) plaques and neurofibrillary tangles. Activated microglia cluster around Aβ deposits, producing pro-inflammatory cytokines that contribute to neuronal dysfunction and death.

Emerging evidence suggests that Type III interferon signaling may modulate this neuroinflammatory response. In AD mouse models, IL-28A treatment has been shown to:

• Reduce microglial activation around amyloid plaques
• Decrease production of pro-inflammatory cytokines (TNF-α, IL-1β)
• Improve cognitive performance in behavioral testing
• Reduce synaptic loss in hippocampal regions

Neuroinflammation in Parkinson's Disease

Parkinson's disease involves progressive loss of dopaminergic neurons in the substantia nigra pars compacta, accompanied by microglial activation and neuroinflammation. Type III interferons have shown neuroprotective properties in PD models.

Research by Li et al. (2019) demonstrated that Type III interferon signaling protects dopaminergic neurons from neurodegeneration in both in vitro and in vivo models of PD[@li2019]. The protective mechanism involved:

• Inhibition of microglial activation
• Reduction in pro-inflammatory cytokine production
• Suppression of oxidative stress
• Preservation of dopaminergic neuron viability

Viral-Induced Neuroinflammation

Type III interferons play a critical role in antiviral immunity within the CNS. Research by Birmingham et al. (2013) demonstrated that Type III interferon signaling restricts viral encephalitis, protecting the brain from excessive inflammation-mediated damage[@birmingham2013].

This antiviral function has implications for understanding how chronic viral infections might contribute to neurodegeneration. Several viruses have been implicated in neurodegenerative processes, including:

• Herpes simplex virus type 1 (HSV-1)
• Human herpesvirus 6 (HHV-6)
• Epstein-Barr virus (EBV)
• SARS-CoV-2 (COVID-19)

Signaling Pathway

The canonical IL-28A signaling pathway involves:

Therapeutic Implications

Neurodegenerative Disease Therapy

The neuroprotective and anti-inflammatory properties of IL-28A make it an attractive therapeutic target for neurodegenerative diseases. Several approaches are being explored:

• Recombinant IL-28A protein: Direct administration of IL-28A to enhance neuroprotective signaling
• Agonists of IL28R1: Small molecule or antibody-based agonists that selectively activate Type III interferon signaling
• Gene therapy: Viral vector-mediated expression of IL28A in the CNS

Autoimmune and Inflammatory Disorders

Given its immunomodulatory properties, IL-28A is also being investigated for autoimmune disease applications. The cytokine appears to promote regulatory immune phenotypes while suppressing pro-inflammatory responses, suggesting potential utility in conditions such as:

• Multiple sclerosis (MS)
• Rheumatoid arthritis
• Inflammatory bowel disease (IBD)

Cancer Immunotherapy

Type III interferons, including IL-28A, have emerging roles in cancer immunotherapy. The cytokine can enhance anti-tumor immunity while potentially avoiding the toxicities associated with Type I interferon administration. Clinical trials are evaluating IL-28A-based approaches in various malignancies.

Expression Patterns

Tissue Distribution

IL28A expression is induced primarily in epithelial cells and certain immune cell populations in response to viral infection. Unlike Type I interferons, which are expressed ubiquitously, Type III interferon expression shows more restricted tissue specificity:

| Tissue/Cell Type | Expression Level |
|-----------------|------------------|
| Lung epithelium | High |
| Liver | High |
| Intestinal epithelium | High |
| Brain (neurons, astrocytes, microglia) | Moderate |
| Peripheral blood mononuclear cells | Low to moderate |
| Skin | Moderate |

CNS Expression

Within the brain, IL28A expression is induced during:

• Viral infections (HSV-1, HHV-6, SARS-CoV-2)
• Neuroinflammatory conditions
• Neurodegenerative disease states

Regulation of Expression

IL28A expression is induced by:

• Viral RNA and DNA sensing via RIG-I and cGAS pathways
• Type I interferon signaling (cross-induction)
• NF-κB activation
• Certain cytokine signals (IL-1β, TNF-α)

• Glucocorticoids
• Immunosuppressive cytokines (IL-10, TGF-β)
• Negative regulators of interferon signaling

Genetic Associations

Polymorphisms and Disease

Genetic variation in the IL28A gene region has been associated with:

• Hepatitis C treatment response: SNPs in the IFNL3/IL28B region predict responsiveness to interferon-based therapies
• COVID-19 severity: Certain IL28B variants associated with disease outcomes
• Autoimmune disease susceptibility: Genetic links to multiple sclerosis and inflammatory bowel disease

Population Genetics

The IFNL gene cluster shows substantial haplotype diversity across human populations, with certain variants reaching high frequencies in specific ethnic groups. This variation has implications for personalized medicine approaches targeting the Type III interferon system.

See Also

• [Interleukin-28B (IL28B/IFNL3)](/genes/il28b) — Related Type III interferon
• [Interleukin-29 (IL29/IFNL1)](/genes/il29) — Another Type III interferon family member
• [Type I Interferons (IFN-α/β)](/mechanisms/interferon-signaling) — Related interferon family
• [Microglia](/cell-types/microglia) — CNS immune cells expressing IL28R1
• [Neuroinflammation](/mechanisms/neuroinflammation) — Inflammatory processes in the CNS
• [Alzheimer's Disease](/diseases/alzheimers-disease) — Neurodegenerative disease context
• [Parkinson's Disease](/diseases/parkinsons-disease) — Neurodegenerative disease context

External Links

• [Ensembl: ENSG00000183709](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000183709)
• [NCBI Gene: IL28A](https://www.ncbi.nlm.nih.gov/gene/282616)
• [GeneCards: IL28A](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL28A)
• [OMIM: 607401](https://omim.org/entry/607401)
• [UniProt: Q8IZJ0](https://www.uniprot.org/uniprot/Q8IZJ0)
• [Allen Brain Atlas: IL28A Expression](https://human.brain-map.org/microarray/search/show?search_term=IL28A)
• [PubMed: Type III Interferons in CNS](https://pubmed.ncbi.nlm.nih.gov/?term=IFN-lambda+neuroinflammation+Alzheimer+Parkinson)

References