Interleukin 26

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.

IL-26R, a conventional receptor for IL-26, consists in two chains required for signaling – IL-10R2, and IL-20R1.[12] The IL-20R1 subunit contains the IL-26-binding site.

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 source of IL-26. More accurately, IL-26 is expressed by pro-inflammatory IL-17 producing T cells in chronically inflamed tissues.[13][14][15] 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).[16] 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.[17]

It remains unclear whether IL-26 is expressed by monocytes and macrophages. Some studies showed there is no expression,[18] whereas other studies inconsistently reported constitutive expression at a low level in monocytes,[19] and the secretion of IL-26 by lung alveolar macrophages locally exposed to endotoxin.[20]

Regarding non-immune cells, IL-26 expression was detected in primary bronchial epithelial cells from healthy individuals.[21] Pathologically, IL-26 is over-expressed in the joints of patients suffering from spondyloarthritis[22] and rheumatoid arthritis.[15]

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,[23] 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.

Most biological functions of IL-26 have been identified in pathological situations that feature chronic inflammation. The expression of IL-26 is elevated in 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.[13]

IL-26 is a natural human antimicrobial that promotes immune sensing of bacterial and host cell death. IL-26, a human Th17 cell–derived cytokine, 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.[23]

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.[16]  

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