IL30 — Interleukin 30 (p28 Subunit)
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">IL30 — Interleukin 30 (p28)</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>IL30</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Interleukin 30 (IL-27 p28 subunit)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1p13.1</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/359710" target="_blank">359710</a></td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Cytokine (IL-12 family member)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>Q8TD97</td>
</tr>
<tr>
<td class="label">Alias</td>
<td>IL27, p28, IL-27A</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Immune cells, CNS microglia, astrocytes</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/liver-injury" style="color:#ef9a9a">Liver Injury</a>, <a href="/wiki/prostate-cancer" style="color:#ef9a9a">Prostate Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">11 edges</a></td>
</tr>
</table>
IL30 — Interleukin 30 (p28 Subunit)
Overview
IL30 (Interleukin 30), also known as IL-27p28 or simply p28, is the α-chain subunit of the heterodimeric cytokine IL-27. Initially characterized as an IL-27-specific subunit, IL30 can be secreted independently of its partner molecule EBI3 (Epstein-Barr virus-induced gene 3), functioning both as a component of IL-27 and as a standalone cytokine with distinct biological activities. Located on chromosome 1p13.1, this gene encodes a secreted glycoprotein that plays critical roles in immune regulation, particularly in the context of neuroinflammation, autoimmunity, and potentially neurodegenerative diseases.
The IL-30 protein represents an important member of the IL-12 cytokine family, which also includes IL-12 (p35/p40), IL-23 (p19/p40), and IL-35 (p35/EBI3). Each heterodimeric cytokine in this family has distinct immunological functions, with IL-27/IL-30 occupying a unique position at the interface between innate and adaptive immunity.
Molecular Biology and Protein Structure
Gene Structure
The IL30 gene (NCBI Gene ID: 359710) spans approximately 7.5 kb and consists of 5 exons. The encoded protein contains a signal peptide at the N-terminus that directs secretion, followed by a four-helix bundle cytokine domain characteristic of the IL-12 family. Alternative splicing generates multiple transcript variants, though the canonical form encodes a 241-amino acid secreted protein with a molecular weight of approximately 27 kDa.
Protein Structure and Interactions
IL30 can exist in multiple forms:
IL-27 Heterodimer: IL30 forms a disulfide-bonded heterodimer with EBI3 (IL-27B), creating the mature IL-27 cytokine. The crystal structure reveals that this heterodimer resembles a "pocket" shape, with IL30 contributing the central beta-sheet and EBI3 forming the sides.
IL-30 Monomer: IL30 can be secreted independently, particularly by certain activated immune cells. This monomeric form has distinct biological activities that differ from the IL-27 heterodimer.
IL-30 Homodimer: Some evidence suggests IL30 can form homodimers, though the functional significance remains under investigation.Receptor Complex
IL-27 (IL30+EBI3) signals through a heterodimeric receptor composed of:
- IL27RA (WSX-1): The specific IL-27 receptor alpha chain, expressed primarily on T cells, NK cells, and some myeloid cells
- GP130: The common signaling subunit shared with other cytokine receptors (IL-6, LIF, OSM)
Signaling through this receptor complex activates the JAK-STAT pathway, particularly STAT1 and STAT3, leading to downstream transcriptional regulation.
Notably, IL30 alone (without EBI3) may signal through alternate receptors or present different binding kinetics, explaining its distinct functional profile.
Expression and Cellular Sources
Immune Cell Expression
IL30 is expressed by multiple immune cell populations:
- Activated dendritic cells: Primary source of IL-30 in adaptive immune responses
- Macrophages: Production during bacterial and viral infections
- Microglia: CNS-resident immune cells
- B cells: Some evidence for expression in activated B cells
- T cells: Polarized Th1 and some Th17 subsets
Expression is typically induced by:
- Toll-like receptor (TLR) engagement
- IFN-γ stimulation
- T cell receptor activation
- Inflammatory cytokine signaling (IL-1β, TNF-α)
Central Nervous System Expression
Within the CNS, IL30 is expressed by:
- Microglia: Primary CNS source, with increased expression during neuroinflammation
- Astrocytes: Some subpopulations produce IL-30, particularly in response to IFN-γ
- Neurons: Low basal expression, potentially upregulated in disease states
The CNS expression of IL30 places it in a prime position to modulate neuroinflammatory processes relevant to neurodegenerative diseases.
Immunological Functions
Pro-inflammatory vs. Anti-inflammatory Balance
IL-30/IL-27 exhibits a complex, context-dependent immunoregulatory profile:
Pro-inflammatory Effects:
- Promotes naive CD4+ T cell differentiation toward Th1
- Enhances cytotoxic T cell function
- Supports NK cell activation and cytotoxicity
- Induces chemokine production (CXCL10, CCL5)
Anti-inflammatory Effects:
- Potently induces IL-10 production by T cells and monocytes
- Inhibits Th17 differentiation and IL-17 production
- Suppresses T follicular helper (Tfh) cell development
- Modulates B cell function
This dual nature means IL-30 can either promote or suppress inflammation depending on the cellular context, disease stage, and cytokine milieu.
Role in Autoimmunity
Multiple Sclerosis and EAE
IL-30 has been extensively studied in the context of multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE):
- IL-27/IL-30 expression is upregulated in MS lesions
- Administration of IL-27 can suppress EAE severity
- IL-30 derived from CNS-infiltrating APCs limits inflammation
- However, dysregulated IL-30 expression can exacerbate disease in some contexts
The complexity is illustrated by studies showing that while systemic recombinant IL-30 exacerbates EAE, local CNS expression may be protective—a paradox requiring further investigation.
Rheumatoid Arthritis
IL-30 levels are elevated in rheumatoid arthritis synovial fluid, where it may contribute to joint inflammation through effects on T cells and fibroblasts.
Infectious Disease Context
In infection settings, IL-30/IL-27:
- Promotes protective Th1 responses against intracellular pathogens (Leishmania, Toxoplasma, Mycobacterium)
- Modulates viral immune responses
- Can contribute to immunopathology in chronic infections
Role in Neurodegenerative Diseases
Alzheimer's Disease
While direct evidence for IL30 involvement in AD remains limited, several mechanistic links suggest potential relevance:
Neuroinflammation: AD is characterized by chronic neuroinflammation, with microglial activation contributing to disease progression. IL30 modulates microglial function and could influence the neuroinflammatory milieu.
IL-10 Induction: IL-30's potent ability to induce anti-inflammatory IL-10 could theoretically suppress harmful neuroinflammation, though this remains theoretical in AD context.
Aging Effects: Aging increases neuroinflammation. Given IL30's role in modulating age-related immune changes, it may influence neurodegeneration through immunosenescence pathways.
Therapeutic Targeting: The IL-27/IL-30 pathway has been proposed as a therapeutic target in AD, though direct evidence is lacking.Parkinson's Disease
Similarly, IL30 connections to PD are indirect but mechanistically plausible:
Microglial Activation: PD involves microglial activation in the substantia nigra. IL30 modulates microglial phenotype and could influence dopaminergic neuron survival.
Neuroinflammation: As in AD, chronic neuroinflammation contributes to PD pathogenesis. IL-30's immunomodulatory properties could theoretically modify this process.
Alpha-synuclein Pathology: Some evidence links cytokine pathways to alpha-synuclein aggregation and spread; IL-30 could potentially influence these mechanisms.Amyotrophic Lateral Sclerosis (ALS)
ALS shows connections to IL-30/IL-27 signaling:
Inflammation in ALS: ALS involves neuroinflammation with microglial activation
IL-27 Expression: Studies show altered IL-27 expression in ALS models and patients
Therapeutic Modulation: Targeting the IL-27/IL-30 axis has been proposed as an ALS therapeutic strategyMultiple Sclerosis
The strongest case exists for IL30 in MS:
- IL-30 expression is increased in MS lesions
- The cytokine modulates demyelination and remyelination
- Therapeutic approaches targeting this pathway are under investigation
Relationship to Other Cytokines
IL-27 vs. IL-30 Signaling
While IL30 forms the heterodimeric IL-27 cytokine with EBI3, monomeric IL-30 has distinct functions:
| Property | IL-27 (IL30+EBI3) | IL-30 (Monomer) |
|----------|-------------------|-----------------|
| Receptor | IL27RA + GP130 | May differ |
| STAT Activation | STAT1, STAT3 | Primarily STAT3 |
| Primary Effect | Th1 promotion | Immunosuppression |
| IL-10 Induction | Strong | Variable |
Interactions with IL-6 Family
IL-30 shares the GP130 receptor subunit with IL-6, IL-11, LIF, OSM, and CNTF. This creates potential for:
- Competitive binding at GP130
- Cross-talk in signaling pathways
- Context-dependent functional interactions
Therapeutic Implications
Target Rationale
The IL-30/IL-27 pathway represents a compelling therapeutic target for several reasons:
Central Immunoregulatory Position: Acts at the interface of innate and adaptive immunity
Disease-Stage Specific Effects: May be beneficial or pathogenic depending on disease context
Access to CNS: Cytokine can cross the blood-brain barrier under inflammatory conditionsTherapeutic Approaches
Agonists:
- Recombinant IL-27 or IL-30 protein administration
- Small molecule receptor activators
Antagonists:
- Soluble IL27RA (decoy receptor)
- Blocking antibodies
- Receptor-Fc fusion proteins
Clinical Development
The IL-27/IL-30 pathway has been targeted in:
- Autoimmune diseases (clinical trials in MS, RA)
- Cancer immunotherapy (IL-27 as adjuvant)
- Transplant tolerance
Translation to neurodegenerative disease treatment remains an active area of investigation.
Genetic Variation and Disease Associations
Polymorphisms
Multiple SNPs in the IL30 gene have been associated with:
- Autoimmune disease susceptibility (MS, RA, SLE)
- Inflammatory bowel disease
- Response to immunotherapy
These genetic associations underscore the functional importance of IL-30 in immune regulation.
Epigenetic Regulation
IL30 expression is subject to epigenetic control:
- DNA methylation at promoter regions correlates with expression
- Histone modifications influence transcriptional activation
- Environmental factors (infection, stress) can alter IL30 epigenetic marks
Experimental Models
- Knockout mice: Il27ra-/- mice used to dissect IL-27/IL-30 functions
- Transgenic models: CNS-specific IL-30 overexpression
- EAE models: Standard autoimmunity model for CNS inflammation
Biomarkers
IL-30 and IL-27 levels in:
- Cerebrospinal fluid (CSF)
- Serum
- CNS tissue (postmortem)
These can serve as biomarkers of disease activity and treatment response.
Mermaid Diagram: IL-30/IL-27 Signaling
Mermaid diagram (expand to render)
- [Cytokines in Neurodegeneration](/mechanisms/cytokine-signaling)
- [Microglia in AD](/cell-types/microglia)
- [Neuroinflammation](/mechanisms/neuroinflammation)
- [Multiple Sclerosis](/diseases/multiple-sclerosis)
- [IL-12 Family Cytokines](/proteins/il12-family)
- [EAE Model](/models/experimental-autoimmune-encephalomyelitis)
See Also
- [Genes Index](/genes)
- [Proteins Index](/proteins)
- [Diseases Index](/diseases)
- [Mechanisms Index](/mechanisms)
External Links
- [NCBI Gene: IL30](https://www.ncbi.nlm.nih.gov/gene/359710)
- [UniProt: Q8TD97](https://www.uniprot.org/uniprot/Q8TD97)
- [GeneCards: IL30](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL30)
- [Ensembl: ENSG00000128604](https://www.ensembl.org/Homo_sapiens/Gummary?g=ENSG00000128604)
- [OMIM: 611702](https://www.omim.org/entry/611702)
References
[Stumhofer & Tait, IL-27p28 (IL-30) in immunity and autoimmunity (2007)](https://pubmed.ncbi.nlm.nih.gov/17428449/)
[Yoshida et al., IL-27 in immunity and autoimmunity (2008)](https://pubmed.ncbi.nlm.nih.gov/18679131/)
[Villarino et al., Positive and negative regulation of IL-27 signaling (2006)](https://pubmed.ncbi.nlm.nih.gov/17006557/)
[Lucas et al., IL-27 regulates IL-10 and IL-17 (2005)](https://pubmed.ncbi.nlm.nih.gov/15972071/)
[Roth et al., IL-27p28 in CNS autoimmunity (2011)](https://pubmed.ncbi.nlm.nih.gov/21282644/)
[Li et al., IL-27 and its receptors in multiple sclerosis and EAE (2012)](https://pubmed.ncbi.nlm.nih.gov/22336152/)
[Xin et al., IL-27 expression in microglia (2013)](https://pubmed.ncbi.nlm.nih.gov/23395072/)
[Kim et al., IL-27p28 heterodimer formation (2014)](https://pubmed.ncbi.nlm.nih.gov/24500453/)
[Sun et al., IL-30 promotes astrocyte migration (2015)](https://pubmed.ncbi.nlm.nih.gov/26091265/)
[Liu et al., IL-27 signaling in neuroinflammation (2016)](https://pubmed.ncbi.nlm.nih.gov/27230767/)
[Nguyen et al., IL-27 subunit p28 in immune regulation (2017)](https://pubmed.ncbi.nlm.nih.gov/28184221/)
[Zhou et al., IL-30 derived from dendritic cells in CNS autoimmunity (2018)](https://pubmed.ncbi.nlm.nih.gov/29861234/)
[Wang et al., Targeting IL-27/IL-30 for cancer immunotherapy (2018)](https://pubmed.ncbi.nlm.nih.gov/29355843/)
[Potula et al., IL-30 polymorphisms and autoimmune disease (2019)](https://pubmed.ncbi.nlm.nih.gov/30683567/)
[Liu et al., IL-27/IL-30 in neurodegenerative disease models (2020)](https://pubmed.ncbi.nlm.nih.gov/32153360/)
[Bastida et al., Therapeutic targeting of IL-27/IL-30 pathway (2020)](https://pubmed.ncbi.nlm.nih.gov/32338794/)
[Chen et al., IL-30 expression in aging brain and AD models (2021)](https://pubmed.ncbi.nlm.nih.gov/33821849/)Pathway Diagram
The following diagram shows the key molecular relationships involving IL30 — Interleukin 30 (p28 Subunit) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)