Interleukin-26 (IL-26) is aprotein that in humans is encoded by theIL26gene.[3][4][5]
IL-26 is the most recently identified member of theIL-20 cytokine subfamily,[6] which was formed according to the usage of common receptor subunits and similarities in target-cell profiles and functions. Allcytokines belonging to this subfamily are members of the largerIL-10 family. IL-26 is expressed in certainherpesvirus-transformedT cells but not in primary stimulated T cells.[4] IL-26 signals through a receptor complex comprising two distinct proteins calledIL-20 receptor 1 andIL-10 receptor 2.[7] By signaling through this receptor complex, IL-26 induces rapidphosphorylation of the transcription factorsSTAT1 andSTAT3, which enhanceIL-10 andIL-8 secretion and as expression of theCD54 molecule on the surface of epithelial cells.[8]
TheIL26 gene is conserved in variousvertebrates, 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 onchromosome 12 (12q15), between the genes encodingIL-22 andIFNγ,[10] and composed of fiveexons separated by threeintrons. Thisgenomic 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 sixalpha helices connected by loops and four conservedcysteine residues. Endogenous IL-26 is expressed as a 36kDa homodimer.[4] Originally named AK155, IL-26 was categorized in theIL-10 cytokine family due to sequence homology and secondary structure similarities.
The IL-26 expression was initially discovered in human HVS-transformed T cells.[6] Since then it was confirmed that T helper 1 cells andTh17 memoryCD4+ cells are the major sources of IL-26. More accurately, IL-26 is expressed by pro-inflammatoryIL-17 producingT 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 ofgraft-versus-host disease (GvHD).[15] CD4+ T cells polarized toward a regulatory phenotype(Treg), naïve CD4+ T cells, andT helper 2 cells show low or no expression of IL-26.[16]
IL-26Rheterodimer, 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 withepithelial cells suggested both receptor subunits are required for the IL-26-dependentsignal transduction.[8] According to some observations,[20] there is a possibility that additional IL-26 receptors exist.
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.
Interleukin 26 (IL-26) is an inflammatory mediator and a driver ofchronic 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 cationicamphipathic 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 oftype I interferon byplasmacytoid dendritic cells via activation ofToll-like receptor 9, but independently of the IL-26 receptor.[22] Monocytes infected withintracellular bacteriumMycobacterium tuberculosis reacted by decreasing IL-26 production, and IL-26 serum concentrations were lower intuberculosis 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 byhepatitis 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 withCrohn's disease and it was reported that IL-26 induces the expression ofIL-8 andTNFα as well asIL-10 in human gut epithelial cells. This activation of epithelial cells involvesSTAT1 and/orSTAT3.[12]IL26 gene is also over-expressed in the joints of patients withspondyloarthritis[24] andrheumatoid 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 humankeratinocyte proliferation in response to IL-26 has been detected.
^Goris A, Marrosu MG, Vandenbroeck K (August 2001). "Novel polymorphisms in the IL-10 related AK155 gene (chromosome 12q15)".Genes and Immunity.2 (5):284–6.doi:10.1038/sj.gene.6363772.PMID11528524.S2CID11291286.
^Igawa D, Sakai M, Savan R (March 2006). "An unexpected discovery of two interferon gamma-like genes along with interleukin (IL)-22 and -26 from teleost: IL-22 and -26 genes have been described for the first time outside mammals".Molecular Immunology.43 (7):999–1009.doi:10.1016/j.molimm.2005.05.009.PMID16005068.
^Qi ZT, Nie P (November 2008). "Comparative study and expression analysis of the interferon gamma gene locus cytokines in Xenopus tropicalis".Immunogenetics.60 (11):699–710.doi:10.1007/s00251-008-0326-y.PMID18726591.S2CID25613652.
^Che KF, Tengvall S, Levänen B, Silverpil E, Smith ME, Awad M, et al. (November 2014). "Interleukin-26 in antibacterial host defense of human lungs. Effects on neutrophil mobilization".American Journal of Respiratory and Critical Care Medicine.190 (9):1022–31.doi:10.1164/rccm.201404-0689OC.PMID25291379.
^Hummelshoj L, Ryder LP, Poulsen LK (July 2006). "The role of the interleukin-10 subfamily members in immunoglobulin production by human B cells".Scandinavian Journal of Immunology.64 (1):40–7.doi:10.1111/j.1365-3083.2006.01773.x.PMID16784489.S2CID46419911.
^Nagalakshmi ML, Murphy E, McClanahan T, de Waal Malefyt R (May 2004). "Expression patterns of IL-10 ligand and receptor gene families provide leads for biological characterization".International Immunopharmacology. IL-Teenagers; the family of the IL-10 homologue comes of age.4 (5):577–92.doi:10.1016/j.intimp.2004.01.007.PMID15120644.
^Miot C, Beaumont E, Duluc D, Le Guillou-Guillemette H, Preisser L, Garo E, et al. (September 2015). "IL-26 is overexpressed in chronically HCV-infected patients and enhances TRAIL-mediated cytotoxicity and interferon production by human NK cells".Gut.64 (9):1466–75.doi:10.1136/gutjnl-2013-306604.PMID25183206.S2CID8052342.
^Heftdal LD, Andersen T, Jæhger D, Woetmann A, Østgård R, Kenngott EE, et al. (July 2017). "Synovial cell production of IL-26 induces bone mineralization in spondyloarthritis".Journal of Molecular Medicine.95 (7):779–787.doi:10.1007/s00109-017-1528-2.PMID28365787.S2CID3932106.
^Michalak-Stoma A, Pietrzak A, Szepietowski JC, Zalewska-Janowska A, Paszkowski T, Chodorowska G (December 2011). "Cytokine network in psoriasis revisited".European Cytokine Network.22 (4):160–8.doi:10.1684/ecn.2011.0294.PMID22236965.
^Esendagli G, Kurne AT, Sayat G, Kilic AK, Guc D, Karabudak R (February 2013). "Evaluation of Th17-related cytokines and receptors in multiple sclerosis patients under interferon β-1 therapy".Journal of Neuroimmunology.255 (1–2):81–4.doi:10.1016/j.jneuroim.2012.10.009.PMID23177721.S2CID11325105.
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