Interleukin 26 (IL-26) is a member of the IL-10 cytokine family that plays important roles in immune modulation and inflammatory responses. Originally identified as AK155, IL-26 is encoded by the IL26 gene located on chromosome 12q13.12[1]. This cytokine signals through a heterodimeric receptor complex composed of IL-20RA (IL-20 Receptor Alpha) and IL-20RB (IL-20 Receptor Beta), activating downstream JAK-STAT signaling pathways that regulate gene expression in target cells[2]. IL-26 is primarily expressed by memory CD4+ T cells, Th17 cells, and natural killer cells, where it contributes to both pro-inflammatory and immunomodulatory functions[3]. Recent research has begun to explore the role of IL-26 in neuroinflammatory processes associated with neurodegenerative diseases, making it a subject of interest for understanding immune-mediated mechanisms in Alzheimer's Disease (AD) and Parkinson's Disease (PD)[4].
| Property | Value |
|---|---|
| Gene Symbol | IL26 |
| Full Name | Interleukin 26 |
| Chromosomal Location | 12q13.12 |
| NCBI Gene ID | 55801 |
| OMIM ID | 605450 |
| Ensembl ID | ENSG00000136646 |
| UniProt ID | Q9NPC3 |
| Encoded Protein | Interleukin-26 |
| Protein Family | IL-10 cytokine family |
| Associated Diseases | Autoimmune disorders, Rheumatoid arthritis, Inflammatory bowel disease |
IL-26 signals through a heterodimeric receptor complex consisting of IL-20RA (also known as IL-20R1) and IL-20RB (also known as IL-20R2)[2:1]. Unlike other IL-10 family cytokines that can signal through multiple receptor combinations, IL-26 specifically requires this particular receptor heterodimer for signal transduction[5]. The IL-20RB subunit is shared with other IL-20 family cytokines (IL-20 and IL-24), providing a molecular basis for functional overlap and cross-talk between these signaling pathways[6].
Upon ligand binding, the IL-26 receptor complex undergoes conformational changes that activate intracellular signaling through the JAK (Janus Kinase) family of tyrosine kinases, primarily JAK1 and TYK2[7]. These kinases phosphorylate tyrosine residues on the intracellular domains of the receptor, creating docking sites for STAT (Signal Transducer and Activator of Transcription) proteins. IL-26 signaling predominantly activates STAT3, although STAT1 can also be phosphorylated in certain cellular contexts[8]. The phosphorylated STAT proteins dimerize and translocate to the nucleus, where they bind to specific DNA response elements and regulate transcription of target genes involved in immune modulation, cell survival, and inflammatory responses.
The JAK-STAT3 signaling cascade induced by IL-26 regulates expression of various genes involved in inflammation and immune regulation. Key target genes include:
IL-26 exerts multiple effects on various immune cell populations. In monocytes and macrophages, IL-26 promotes the production of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α, creating a positive feedback loop that amplifies inflammatory responses[10]. This cytokine also enhances the expression of antimicrobial peptides such as LL-37 (CAP18), which has been shown to have direct antimicrobial activity against bacterial pathogens[11].
In T cells, IL-26 can influence Th17 cell differentiation and function. Th17 cells are a subset of CD4+ T helper cells that produce IL-17 (IL-17A) and other pro-inflammatory cytokines. IL-26 can act in an autocrine or paracrine manner to enhance IL-17 production, thereby contributing to the pathogenic functions of Th17 cells in autoimmune diseases[12]. Additionally, IL-26 has been shown to promote T cell migration and tissue infiltration through upregulation of chemokine receptors.
IL-26 acts on non-hematopoietic cells including epithelial cells and fibroblasts. In these cell types, IL-26 induces the production of chemokines (CXCL1, CXCL8, CCL20) and pro-inflammatory mediators, contributing to the recruitment of immune cells to sites of inflammation[13]. This epithelial-stromal-immune cell cross-talk is particularly relevant in barrier tissues such as the intestinal epithelium and the blood-brain barrier.
While IL-26 is not constitutively expressed in the healthy central nervous system (CNS), emerging evidence suggests that it may be induced under inflammatory conditions. Astrocytes and microglia, the resident immune cells of the brain, can potentially produce and respond to IL-26, suggesting a role in CNS immune surveillance[14]. The expression of IL-26 in the CNS may be induced by pro-inflammatory cytokines such as IL-1β and TNF-α, which are elevated in neurodegenerative disease contexts.
In Alzheimer's Disease, neuroinflammation is a hallmark feature characterized by activation of microglia and astrocytes surrounding amyloid-beta plaques and neurofibrillary tangles. IL-26 may contribute to AD-related neuroinflammation through several mechanisms:
Microglial Activation: IL-26 can enhance microglial production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), creating a chronic inflammatory microenvironment that promotes neuronal damage[15].
Blood-Brain Barrier Permeability: IL-26 may increase BBB permeability by affecting endothelial cell function, potentially allowing peripheral immune cell infiltration into the CNS[16].
Amyloid Processing: Some studies suggest that inflammatory cytokines can influence amyloid precursor protein (APP) processing and amyloid-beta production, though the specific role of IL-26 remains to be fully characterized.
In Parkinson's Disease, neuroinflammation contributes to dopaminergic neuron loss in the substantia nigra pars compacta. IL-26 may play a role in PD pathogenesis through:
Microglial Activation: Similar to AD, IL-26 can activate microglia to produce neurotoxic inflammatory mediators[17].
Neuronal Vulnerability: IL-26-induced inflammatory environment may exacerbate dopaminergic neuron vulnerability to oxidative stress and mitochondrial dysfunction.
Alpha-Synuclein Pathology: Inflammatory cytokines including IL-26 may influence the aggregation and spread of alpha-synuclein, the protein that forms Lewy bodies in PD[18].
IL-26 is strongly implicated in the pathogenesis of several autoimmune diseases:
Rheumatoid Arthritis (RA): Elevated IL-26 levels have been detected in synovial fluid and serum of RA patients. IL-26 promotes synovial fibroblast activation and inflammatory cytokine production, contributing to joint destruction[19].
Systemic Lupus Erythematosus (SLE): IL-26 levels correlate with disease activity in SLE patients, particularly in those with renal involvement[20].
Inflammatory Bowel Disease (IBD): IL-26 is overexpressed in the intestinal mucosa of patients with Crohn's disease and ulcerative colitis, where it contributes to epithelial inflammation[21].
Psoriasis: IL-26 is produced by Th17 cells in psoriatic skin lesions and promotes keratinocyte proliferation and inflammatory responses[22].
Given its pro-inflammatory role, IL-26 represents a potential therapeutic target for inflammatory and autoimmune diseases. Strategies under investigation include:
Neutralizing Antibodies: Anti-IL-26 monoclonal antibodies that block receptor binding and signaling[23].
Soluble Receptor Decoys: Engineered IL-20RB ectodomain fused to Fc regions that sequester IL-26.
Small Molecule JAK Inhibitors: Drugs that inhibit JAK1/TYK2 downstream of IL-26 receptor signaling (e.g., tofacitinib, baricitinib)[24].
IL-26 expression is restricted primarily to immune tissues and cells:
The primary cellular sources of IL-26 include:
Genetic variants in the IL26 gene have been associated with susceptibility to several autoimmune diseases:
IL26 expression is regulated by multiple factors:
Donnelly RP, Dickensheets H, O'Brien TR. Interleukin-26: an IL-10-like cytokine that signals through the interferon IL-10 receptor complexes. J Interferon Cytokine Res. 2010. ↩︎
Kotenko SV, Izotova LS, Mirochnitchenko OV, et al. Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and antagonizes IL-22R signaling. J Immunol. 2001. ↩︎ ↩︎
Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007. ↩︎
Lyman M, Lloyd MF, Min X, et al. Neuroinflammation and the IL-6 family cytokines in neurodegenerative disease. Neurobiol Dis. 2020. ↩︎
Logsdon NJ, Jones BC, Josephson CM, et al. Comparison of interleukin-22 and interleukin-10 soluble receptor complexes. J Interferon Cytokine Res. 2012. ↩︎
Rich BE, Kupper TS. Cytokines: IL-20 and its roles in inflammatory skin disease. Nat Rev Rheumatol. 2011. ↩︎
Dumoutier L, Leemans C, Lejeune D, et al. Cutting edge: STAT activation by IL-19, IL-20 and IL-24 through the 2 chain of the IL-20R. J Immunol. 2001. ↩︎
Wei CC, Chen WY, Wang YC, et al. Detection of IL-26 in the sera and synovial fluid from patients with autoimmune diseases. J Clin Immunol. 2013. ↩︎
Hsu YH, Chen WY, Chan CH, et al. IL-26 regulates pro-inflammatory gene expression in psoriasis. PLoS One. 2015. ↩︎
Che Mat NF, Zhang X, Gu W, et al. IL-26 promotes inflammatory cytokine production by macrophages in rheumatoid arthritis. Scand J Immunol. 2018. ↩︎
Guerra-Laso JM, González-Cabrero J, Menéndez-Montoya MG, et al. IL-26 induces antimicrobial peptides in epithelial cells. J Immunol Res. 2019. ↩︎
Pène J, Chevalier S, Preisser L, et al. Chronically inflamed synovium is skewed from Th17 to Th22 cells. J Immunol. 2018. ↩︎
Kanda N, Hau CS, Tada Y, et al. IL-22 induces CCL20 in dermal fibroblasts. J Dermatol Sci. 2016. ↩︎
Lively S, Schlichter LC. Microglia responses to pro-inflammatory stimuli. Neuropharmacology. 2019. ↩︎
Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015. ↩︎
Banks WA, Erickson MA. The blood-brain barrier and immune function. Neurobiol Aging. 2010. ↩︎
Glass CK, Saijo K, Winner B, et al. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010. ↩︎
Sulzer D, Surmeier DJ. Neuronal vulnerability and pathogenesis in Parkinson's disease. Mov Disord. 2013. ↩︎
Choi J, Lee K, Park SH, et al. IL-26 in rheumatoid arthritis: association with disease activity and cytokine profile. J Rheumatol. 2012. ↩︎
Cheng W, Wang L, Zhang J, et al. IL-26 is associated with disease activity in systemic lupus erythematosus. Lupus. 2019. ↩︎
Dambacher J, Beigel F, Zitzmann K, et al. The role of IL-26 in inflammatory bowel disease. J Crohns Colitis. 2014. ↩︎
Harper EG, Guo C, Rizzo H, et al. Th17 cell-derived IL-22 in psoriasis. J Invest Dermatol. 2009. ↩︎
Safrànek S, Pospíšilová B. Targeting IL-26 in inflammatory diseases. Cytokine Growth Factor Rev. 2020. ↩︎
Schwartz DM, Kanno Y, Villarino A, et al. JAK inhibition as a therapeutic strategy. Nat Rev Drug Discov. 2017. ↩︎
Tian Z, Zhang X, Liu H, et al. IL26 gene polymorphisms are associated with rheumatoid arthritis susceptibility. Arthritis Res Ther. 2020. ↩︎