Interleukin 26

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

IL26
Identifiers
AliasesIL26, AK155, IL-26, interleukin 26
External IDsOMIM: 605679 HomoloGene: 81862 GeneCards: IL26
Gene location (Human)
Chr.Chromosome 12 (human)[1]
Band12q15Start68,201,349 bp[1]
End68,225,810 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

55801

n/a

Ensembl

ENSG00000111536

n/a

UniProt

Q9NPH9

n/a

RefSeq (mRNA)

NM_018402

n/a

RefSeq (protein)

NP_060872

n/a

Location (UCSC)Chr 12: 68.2 – 68.23 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

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.

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.

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 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]

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,[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.

References
  1. GRCh38: Ensembl release 89: ENSG00000111536 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Entrez Gene: interleukin 26".
  4. Knappe A, Hör S, Wittmann S, Fickenscher H (April 2000). "Induction of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with herpesvirus saimiri". Journal of Virology. 74 (8): 3881–7. doi:10.1128/JVI.74.8.3881-3887.2000. PMC 111897. PMID 10729163.
  5. 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. PMID 11528524.
  6. Larochette V, Miot C, Poli C, Beaumont E, Roingeard P, Fickenscher H, et al. (2019-02-12). "IL-26, a Cytokine With Roles in Extracellular DNA-Induced Inflammation and Microbial Defense". Frontiers in Immunology. 10: 204. doi:10.3389/fimmu.2019.00204. PMC 6379347. PMID 30809226.
  7. Sheikh F, Baurin VV, Lewis-Antes A, Shah NK, Smirnov SV, Anantha S, et al. (February 2004). "Cutting edge: IL-26 signals through a novel receptor complex composed of IL-20 receptor 1 and IL-10 receptor 2". Journal of Immunology. 172 (4): 2006–10. doi:10.4049/jimmunol.172.4.2006. PMID 14764663.
  8. Hör S, Pirzer H, Dumoutier L, Bauer F, Wittmann S, Sticht H, et al. (August 2004). "The T-cell lymphokine interleukin-26 targets epithelial cells through the interleukin-20 receptor 1 and interleukin-10 receptor 2 chains". The Journal of Biological Chemistry. 279 (32): 33343–51. doi:10.1074/jbc.M405000200. PMID 15178681.
  9. 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. PMID 16005068.
  10. Donnelly RP, Sheikh F, Dickensheets H, Savan R, Young HA, Walter MR (October 2010). "Interleukin-26: an IL-10-related cytokine produced by Th17 cells". Cytokine & Growth Factor Reviews. IL-10 Family of Cytokines. 21 (5): 393–401. doi:10.1016/j.cytogfr.2010.09.001. PMC 2997847. PMID 20947410.
  11. 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. PMID 18726591.
  12. Sheikh F, Baurin VV, Lewis-Antes A, Shah NK, Smirnov SV, Anantha S, et al. (February 2004). "Cutting edge: IL-26 signals through a novel receptor complex composed of IL-20 receptor 1 and IL-10 receptor 2". Journal of Immunology. 172 (4): 2006–10. doi:10.4049/jimmunol.172.4.2006. PMID 14764663.
  13. Dambacher J, Beigel F, Zitzmann K, De Toni EN, Göke B, Diepolder HM, et al. (September 2009). "The role of the novel Th17 cytokine IL-26 in intestinal inflammation". Gut. 58 (9): 1207–17. doi:10.1136/gut.2007.130112. PMID 18483078. S2CID 3186117.
  14. Pène J, Chevalier S, Preisser L, Vénéreau E, Guilleux MH, Ghannam S, et al. (June 2008). "Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes". Journal of Immunology. 180 (11): 7423–30. doi:10.4049/jimmunol.180.11.7423. PMID 18490742.
  15. Corvaisier M, Delneste Y, Jeanvoine H, Preisser L, Blanchard S, Garo E, et al. (2012-09-25). Marrack P (ed.). "IL-26 is overexpressed in rheumatoid arthritis and induces proinflammatory cytokine production and Th17 cell generation". PLOS Biology. 10 (9): e1001395. doi:10.1371/journal.pbio.1001395. PMC 3463509. PMID 23055831.
  16. Ohnuma K, Hatano R, Aune TM, Otsuka H, Iwata S, Dang NH, et al. (April 2015). "Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes". Journal of Immunology. 194 (8): 3697–712. doi:10.4049/jimmunol.1402785. PMC 4568737. PMID 25786689.
  17. Wolk K, Kunz S, Asadullah K, Sabat R (June 2002). "Cutting edge: immune cells as sources and targets of the IL-10 family members?". Journal of Immunology. 168 (11): 5397–402. doi:10.4049/jimmunol.168.11.5397. PMID 12023331.
  18. Wolk K, Kunz S, Asadullah K, Sabat R (June 2002). "Cutting edge: immune cells as sources and targets of the IL-10 family members?". Journal of Immunology. 168 (11): 5397–402. doi:10.4049/jimmunol.168.11.5397. PMID 12023331.
  19. Guerra-Laso JM, Raposo-García S, García-García S, Diez-Tascón C, Rivero-Lezcano OM (February 2015). "Microarray analysis of Mycobacterium tuberculosis-infected monocytes reveals IL26 as a new candidate gene for tuberculosis susceptibility". Immunology. 144 (2): 291–301. doi:10.1111/imm.12371. PMC 4298423. PMID 25157980.
  20. 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. PMID 25291379.
  21. Che KF, Kaarteenaho R, Lappi-Blanco E, Levänen B, Sun J, Wheelock Å, et al. (October 2017). "Interleukin-26 Production in Human Primary Bronchial Epithelial Cells in Response to Viral Stimulation: Modulation by Th17 cytokines". Molecular Medicine. 23 (1): 247–257. doi:10.2119/molmed.2016.00064. PMC 5653736. PMID 28853490.
  22. 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. PMID 28365787.
  23. Meller S, Di Domizio J, Voo KS, Friedrich HC, Chamilos G, Ganguly D, et al. (September 2015). "T(H)17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26". Nature Immunology. 16 (9): 970–9. doi:10.1038/ni.3211. PMC 4776746. PMID 26168081.

Further reading
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