Interleukin 26

IL26
Identifiers
Aliases	IL26 , AK155, IL-26, interleukin 26
External IDs	OMIM: 605679 HomoloGene: 81862 GeneCards: IL26
Gene location (Human)
Chr.	Chromosome 12 (human)
End	68,225,810 bp
RNA expression pattern
	Top expressed in
	appendix; ; amniotic fluid; ; lymph node; ; thymus; ; rectum; ; gallbladder; ; spleen; ; urinary bladder; ; blood; ; sigmoid colon;
	n/a
	More reference expression data
	n/a
Gene ontology
Molecular function	cytokine activity ;
Cellular component	cytosol ; extracellular space ; extracellular region ;
Biological process	cell-cell signaling ; positive regulation of protein kinase B signaling ; positive regulation of receptor signaling pathway via JAK-STAT ; positive regulation of transcription by RNA polymerase II ; positive regulation of stress-activated MAPK cascade ; positive regulation of ERK1 and ERK2 cascade ; negative regulation of epithelial cell proliferation ; regulation of signaling receptor activity ; cytokine-mediated signaling pathway ;
	Sources:Amigo / QuickGO
Orthologs
	55801
	n/a
	ENSG00000111536
	n/a
	Q9NPH9
	n/a
	NM_018402
	n/a
	NP_060872
	n/a
	Wikidata
View/Edit Human

Last updated December 04, 2023

Interleukin-26 (IL-26) is a protein that in humans is encoded by the IL26 gene.^[3]^[4]^[5]

IL-26 is the most recently identified member of the IL-20 cytokine subfamily,^[6] which was formed according to the usage of common receptor subunits and similarities in target-cell profiles and functions. All cytokines belonging to this subfamily are members of the larger IL-10 family. IL-26 is expressed in certain herpesvirus-transformed T cells but not in primary stimulated T cells.^[4] IL-26 signals through a receptor complex comprising two distinct proteins called IL-20 receptor 1 and IL-10 receptor 2.^[7] By signaling through this receptor complex, IL-26 induces rapid phosphorylation of the transcription factors STAT1 and STAT3, which enhance IL-10 and IL-8 secretion and as expression of the CD54 molecule on the surface of epithelial cells.^[8]

Gene organization and protein structure

The IL26 gene is conserved in various vertebrates, but it is curiously absent in mice and rats. Paralogs of this gene have been identified in several non-mammalian species.^[9] The human gene is located on chromosome 12 (12q15), between the genes encoding IL-22 and IFNγ,^[10] and composed of five exons separated by three introns. This genomic cluster of genes encoding IL-22, IL-26, and IFNγ is present among all vertebrates.^[11]

IL-26 is a 171-amino acid protein that exhibits six alpha helices connected by loops and four conserved cysteine residues. Endogenous IL-26 is expressed as a 36 kDa homodimer.^[4] Originally named AK155, IL-26 was categorized in the IL-10 cytokine family due to sequence homology and secondary structure similarities.

Expression

The IL-26 expression was initially discovered in human HVS-transformed T cells.^[6] Since then it was confirmed that T helper 1 cells and Th17 memory CD4+ cells are the major sources of IL-26. More accurately, IL-26 is expressed by pro-inflammatory IL-17 producing T cells in chronically inflamed tissues.^[12]^[13]^[14] Co-expression of IL-17, IL-22, and IL-26 de facto defines the phenotype of human Th17 cells. Furthermore, CD26+ CD4+ T cells produce IL-26 in a model of graft-versus-host disease (GvHD).^[15] CD4+ T cells polarized toward a regulatory phenotype (Treg), naïve CD4+ T cells, and T helper 2 cells show low or no expression of IL-26.^[16]

It remains unclear whether IL-26 monocytes and macrophages express IL-26. Some studies showed there is no expression,^[16] whereas other studies inconsistently reported constitutive expression at a low level in monocytes,^[17] and the secretion of IL-26 by lung alveolar macrophages locally exposed to endotoxin.^[18] The IL-26 expression is also present in NK cells,^[16] especially NKp44+ human NK cell subset localized in mucosa-associated lymphoid tissue express substantial amounts of IL-26.^[19] Very low IL-26 expression was reported in human herpesvirus 8-transformed B cells.^[4]

Regarding non-immune cells, IL-26 expression was detected in primary bronchial epithelial cells from healthy individuals.^[16] Pathologically, fibroblasts harvested from the inflamed synovia of patients with rheumatoid arthritis constituted the main source of IL-26.^[14]

Receptors

IL-26R heterodimer, a conventional receptor for IL-26, consists of two chains – IL-10R2, and IL-20R1.^[7] The IL-20R1 subunit contains the IL-26-binding site, whereas the IL-10R2 subunit acts as a second chain completing the assembly. Experiments performed with epithelial cells suggested both receptor subunits are required for the IL-26-dependent signal transduction.^[8] According to some observations,^[20] there is a possibility that additional IL-26 receptors exist.

Ligand binding by functional IL-26 receptor complex results in the initiation of a signal transduction pathway involving receptor-associated Janus tyrosine kinases Jak1 and Tyk2. IL-20R1 interacts with Jak1, and IL-10R2 is associated with Tyk2. Ligand-induced heterodimerization of receptor chains promotes cross-activation of Janus kinases, which phosphorylate receptor intracellular domains, leading to the activation of STAT protein family intracellular transcription factors STAT1 and STAT3. In addition, IL-26 activates extracellular signal-regulated kinases (ERK)-1/2, c-Jun N-terminal kinase (JNK), mitogen-activated protein kinases (MAPKs), and protein kinase B (PKB).^[7]

While IL-10R2 is expressed on a wide variety of tissues, the expression of IL-20R1 is limited only to some tissues.^[21] Thus, the ability to respond to IL-26 is restricted by the expression of IL-20R1 subunit.

Role

Interleukin 26 (IL-26) is an inflammatory mediator and a driver of chronic inflammation due to its ability to act as a carrier of extracellular DNA,^[22] and as an antimicrobial molecule through its capacity to form pores in bacterial membranes. These properties suggest that IL-26 can be categorized as a kinocidin.

IL-26 is a natural human antimicrobial that promotes immune sensing of bacterial and host cell death. IL-26 is a cationic amphipathic protein that kills extracellular bacteria via membrane-pore formation. Furthermore, Th17 cell–derived IL-26 formed complexes with bacterial DNA and self-DNA released by dying bacteria and host cells. The IL-26–DNA complexes triggered the production of type I interferon by plasmacytoid dendritic cells via activation of Toll-like receptor 9, but independently of the IL-26 receptor.^[22] Monocytes infected with intracellular bacterium M. tuberculosis reacted by decreasing IL-26 production, and IL-26 serum concentrations were lower in tuberculosis patients.^[17] These data indicate that IL-26 may be involved in host defense against bacteria in more ways.

Concerning host defense to viruses, the role of IL-26 appears to be related to the expression of IL-26R by epithelial cells as these constitute the first barrier against many viruses. Elevated serum levels of IL-26 were detected in patients with chronic infection by hepatitis C virus. Moreover, the sensitivity of NK cells to IL-26 might trigger the ability to kill the virus-infected host cells.^[23]

So far, the role of IL-26 in acute inflammation has not been properly studied, and most biological functions of IL-26 have been identified in pathological situations that feature chronic inflammation. The expression of IL-26 is elevated in the inflamed colonic mucosa of patients with Crohn's disease and it was reported that IL-26 induces the expression of IL-8 and TNFα as well as IL-10 in human gut epithelial cells. This activation of epithelial cells involves STAT1 and/or STAT3.^[12]IL26 gene is also over-expressed in the joints of patients with spondyloarthritis ^[24] and rheumatoid arthritis,^[14] in the sera and lesional skin tissues of psoriasis patients,^[25] and in the sera of multiple sclerosis patients.^[26]

A novel effect of IL-26 produced by donor-derived CD26+ CD4+ T cells on the pathophysiology of pulmonary chronic GVHD was observed in a murine model.^[15]

The roles of IL-26 in normal physiology remain unknown. By contrast to other IL-10 cytokine family members, no induction of primary human keratinocyte proliferation in response to IL-26 has been detected.

Related Research Articles

The T helper cells (T_h cells), also known as CD4⁺ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4⁺ cells are mature T_h cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4⁺ cells determines susceptibility to a broad class of autoimmune diseases.

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. IL-12 family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.

Interleukin 7 (IL-7) is a protein that in humans is encoded by the IL7 gene.

<span class="mw-page-title-main">Interleukin 1 beta</span> Mammalian protein found in Homo sapiens

Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.

Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.

Interleukin 30 (IL-30) forms one chain of the heterodimeric cytokine called interleukin 27 (IL-27), thus it is also called IL27-p28. IL-27 is composed of α chain p28 and β chain Epstain-Barr induce gene-3 (EBI3). The p28 subunit, or IL-30, has an important role as a part of IL-27, but it can be secreted as a separate monomer and has its own functions in the absence of EBI3. The discovery of IL-30 as individual cytokine is relatively new and thus its role in the modulation of the immune response is not fully understood.

Interleukin-22 (IL-22) is protein that in humans is encoded by the IL22 gene.

Interleukin 17 family is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17A transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17A protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.

Type II cytokine receptors, also commonly known as class II cytokine receptors, are transmembrane proteins that are expressed on the surface of certain cells. They bind and respond to a select group of cytokines including interferon type I, interferon type II, interferon type III. and members of the interleukin-10 family These receptors are characterized by the lack of a WSXWS motif which differentiates them from type I cytokine receptors.

T helper 17 cells (T_h17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause T_h17s to actually inhibit T_reg differentiation. However, T_h17s are developmentally distinct from T_h1 and T_h2 lineages. T_h17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic T_h17 cells have been termed as T_reg17 cells.

Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.

Single Ig IL-1-related receptor (SIGIRR), also called Toll/Interleukin-1 receptor 8 (TIR8) or Interleukin-1 receptor 8 (IL-1R8), is transmembrane protein encoded by gene SIGIRR, which modulate inflammation, immune response, and tumorigenesis of colonic epithelial cells.

Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

The IL-10 family is a family of interleukins.

Interleukin 23 (IL-23) is a heterodimeric cytokine composed of an IL-12B (IL-12p40) subunit and an IL-23A (IL-23p19) subunit. IL-23 is part of the IL-12 family of cytokines. The functional receptor for IL-23 consists of a heterodimer between IL-12Rβ1 and IL-23R.

Type 3 innate lymphoid cells (ILC3) are immune cells from the lymphoid lineage that are part of the innate immune system. These cells participate in innate mechanisms on mucous membranes, contributing to tissue homeostasis, host-commensal mutualism and pathogen clearance. They are part of a heterogeneous group of innate lymphoid cells, which is traditionally divided into three subsets based on their expression of master transcription factors as well as secreted effector cytokines - ILC1, ILC2 and ILC3.

Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.

References

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