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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]
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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.
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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]
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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.
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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.
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