<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>
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.
<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>
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].
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.
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:
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.
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:
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.
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.
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:
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:
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:
The canonical IL-28A signaling pathway involves:
The neuroprotective and anti-inflammatory properties of IL-28A make it an attractive therapeutic target for neurodegenerative diseases. Several approaches are being explored:
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:
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.
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 |
Within the brain, IL28A expression is induced during:
IL28A expression is induced by:
Genetic variation in the IL28A gene region has been associated with:
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.