Molecular Medicine

, Volume 23, Issue 1, pp 247–257 | Cite as

Interleukin-26 Production in Human Primary Bronchial Epithelial Cells in Response to Viral Stimulation: Modulation by Th17 cytokines

  • Karlhans Fru Che
  • Riitta Kaarteenaho
  • Elisa Lappi-Blanco
  • Bettina Levänen
  • Jitong Sun
  • Åsa Wheelock
  • Lena Palmberg
  • C. Magnus Sköld
  • Anders Lindén
Research Article


Interleukin (IL)-26 is abundant in human airways and this cytokine is involved in the local immune response to a bacterial stimulus in vivo. Specifically, local exposure to the toll-like receptor (TLR) 4 agonist endotoxin does increase IL-26 in human airways and this cytokine potentiates chemotactic responses in human neutrophils. In addition to T-helper (Th) 17 cells, alveolar macrophages can produce IL-26, but it remains unknown whether this cytokine can also be produced in the airway mucosa per se in response to a viral stimulus. Here, we evaluated whether this is the case using primary bronchial epithelial cells from the airway epithelium in vitro and explored the signaling mechanisms involved, including the modulatory effects of additional Th17 cytokines. Finally, we assessed IL-26 and its archetype signaling responses in healthy human airways in vivo. We found increased transcription and release of IL-26 protein after stimulation with the viral-related double stranded (ds) RNA polyinosinic-polycytidylic acid (poly-IC) and showed that this IL-26 release involved mitogen-activated protein (MAP) kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The release of IL-26 in response to a viral stimulus was modulated by additional Th17 cytokines. Moreover, there was transcription of IL26 mRNA and expression of the protein in epithelial cells of bronchial brush and tissue biopsies respectively after harvest in vivo. In addition, the extracellular IL-26 protein concentrations in bronchoalveolar lavage (BAL) samples did correlate with increased epithelial cell transcription of an archetype intracellular signaling molecule downstream of the IL-26-receptor complex, STAT1, in the bronchial brush biopsies. Thus, our study suggests that viral stimulation causes the production of IL-26 in lining epithelial cells of human airways, structural cells that constitute a critical immune barrier and that this production is modulated by Th17 cytokines.



We thank Jie Ji, M.Sc., Institute of Environmental Medicine, Karolinska Institutet, for assisting with primary bronchial epithelial cells as well as Max Vikström, Unit for Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, for assisting with the statistics. We also thank Emma Åkerlund, Unit for Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institutet for assistance with the western blot assay.

Project funding was obtained from the Swedish Heart-Lung Foundation (No. 20150303), the Swedish Research Council (No. 2016-01653), King Gustav V’s and Queen Victoria’s Freemason Research Foundation (ALF No. 20140309). In addition, federal funding was obtained from Karolinska Institutet and, through the Regional ALF Agreement. Project funding was also obtained from Foundation of the Finnish Anti-Tuberculosis Association. No funding was obtained from the tobacco industry.


  1. 1.
    Donnelly RP, et al. (2010) Interleukin-26: an IL-10-related cytokine produced by Th17 cells. Cytokine Growth Factor Rev. 21:393–401.CrossRefGoogle Scholar
  2. 2.
    Fickenscher H, Pirzer H. (2004) Interleukin-26. Int. Immunopharmacol. 4:609–13.CrossRefGoogle Scholar
  3. 3.
    Ouyang W, Rutz S, Crellin NK, Valdez PA, Hymowitz SG. (2011) Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 29:71–109.CrossRefGoogle Scholar
  4. 4.
    Knappe A, Hor S, Wittmann S, Fickenscher H. (2000) Induction of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with herpesvirus saimiri. J. Virol. 74:3881–7.CrossRefGoogle Scholar
  5. 5.
    Dambacher J, et al. (2009) The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut. 58:1207–17.CrossRefGoogle Scholar
  6. 6.
    Corvaisier M, et al. (2012) IL-26 is overexpressed in rheumatoid arthritis and induces proinflammatory cytokine production and Th17 cell generation. PLoS Biol. 10:e1001395.CrossRefGoogle Scholar
  7. 7.
    Miot C, et al. (2015) IL-26 is overexpressed in chronically HCV-infected patients and enhances TRAIL-mediated cytotoxicity and interferon production by human NK cells. Gut. 64:1466–1475.CrossRefGoogle Scholar
  8. 8.
    Heftdal LD, et al. (2017) Synovial cell production of IL-26 induces bone mineralization in spondyloarthritis. J Mol. Med. 95:779–87.CrossRefGoogle Scholar
  9. 9.
    Che KF, et al. (2014) Interleukin-26 in antibacterial host defense of human lungs. Effects on neutrophil mobilization. Am. J. Respir. Crit. Care Med. 190:1022–31.CrossRefGoogle Scholar
  10. 10.
    Griffiths KL, Khader SA. (2014) Bringing in the cavalry: IL-26 mediates neutrophil recruitment to the lungs. Am. J. Respir. Crit. Care Med. 190:1079–80.CrossRefGoogle Scholar
  11. 11.
    Tengvall S, Che KF, Linden A. (2016) Interleukin-26: an emerging player in host defense and inflammation. J. Innate Immun. 8:15–22.CrossRefGoogle Scholar
  12. 12.
    Meller S, et al. (2015) T(H)17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26. Nat. Immunol. 16:970–9.CrossRefGoogle Scholar
  13. 13.
    Crouse J, Kalinke U, Oxenius A. (2015) Regulation of antiviral T cell responses by type I interferons. Nat. Rev. Immunol. 15:231–42.CrossRefGoogle Scholar
  14. 14.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 413:732–8.CrossRefGoogle Scholar
  15. 15.
    Strandberg K, Palmberg L, Larsson K. (2007) Effect of formoterol and salmeterol on IL-6 and IL-8 release in airway epithelial cells. Respir. Med. 101:1132–9.CrossRefGoogle Scholar
  16. 16.
    Jurk M, et al. (2002) Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat. Immunol. 3:499.CrossRefGoogle Scholar
  17. 17.
    Saleh A, Shan L, Halayko AJ, Kung S, Gounni AS. (2009) Critical role for STAT3 in IL-17A-mediated CCL11 expression in human airway smooth muscle cells. J. Immunol. 182:3357–65.CrossRefGoogle Scholar
  18. 18.
    Bennett BL, et al. (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci. U. S. A. 98:13681–86.CrossRefGoogle Scholar
  19. 19.
    Huynh H, Soo KC, Chow PK, Tran E. (2007) Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol. Cancer Ther. 6:138–46.CrossRefGoogle Scholar
  20. 20.
    Ehrhardt C, et al. (2013) The NF-kappaB inhibitor SC75741 efficiently blocks influenza virus propagation and confers a high barrier for development of viral resistance. Cell. Microbiol. 15:1198–211.CrossRefGoogle Scholar
  21. 21.
    Wang J, et al. (2011) Toll-like receptors expressed by dermal fibroblasts contribute to hypertrophic scarring. J. Cell. Physiol. 226:1265–73.CrossRefGoogle Scholar
  22. 22.
    Forsslund H, et al. (2014) Distribution of T-cell subsets in BAL fluid of patients with mild to moderate COPD depends on current smoking status and not airway obstruction. Chest. 145:711–22.CrossRefGoogle Scholar
  23. 23.
    Kohler M, et al. (2013) Gender differences in the bronchoalveolar lavage cell proteome of patients with chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 131:743–51.CrossRefGoogle Scholar
  24. 24.
    Miller MR, et al. (2005) Standardisation of spirometry. Eur. Respir. J. 26:319–38.CrossRefGoogle Scholar
  25. 25.
    Karimi R, Tornling G, Grunewald J, Eklund A, Skold CM. (2012) Cell recovery in bronchoalveolar lavage fluid in smokers is dependent on cumulative smoking history. PloS One. 7:e34232.CrossRefGoogle Scholar
  26. 26.
    Karvonen HM, et al. (2013) Myofibroblast expression in airways and alveoli is affected by smoking and COPD. Respir. Res. 14:84.CrossRefGoogle Scholar
  27. 27.
    Levanen B, et al. (2013) Altered microRNA profiles in bronchoalveolar lavage fluid exosomes in asthmatic patients. J. Allergy Clin. Immunol. 131:894–903.CrossRefGoogle Scholar
  28. 28.
    Kawai T, Akira S. (2008) Toll-like receptor and RIG-I-like receptor signaling. Ann. N. Y. Acad. Sci. 1143:1–20.CrossRefGoogle Scholar
  29. 29.
    Newton K, Dixit VM. (2012) Signaling in innate immunity and inflammation. Cold Spring Harb. Perspect. Biol. 4:a006049.CrossRefGoogle Scholar
  30. 30.
    Sawyer TK, et al. (2005) Protein phosphorylation and signal transduction modulation: chemistry perspectives for small-molecule drug discovery. Med. Chem. 1:293–319.CrossRefGoogle Scholar
  31. 31.
    Cai C, Chen L, Jiang X, Lu X. (2014) Modeling signal transduction from protein phosphorylation to gene expression. Cancer Inform. 13:59–67.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Kim EK, Choi EJ. (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim. Biophys. Acta. 1802:396–405.CrossRefGoogle Scholar
  33. 33.
    Laan M, Lotvall J, Chung KF, Linden A. (2001) IL-17-induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen-activated protein (MAP) kinases. Br. J. Pharmacol. 133:200–6.CrossRefGoogle Scholar
  34. 34.
    Jin W, Dong C. (2013) IL-17 cytokines in immunity and inflammation. Emerg. Microbes Infect. 2:e60.CrossRefGoogle Scholar
  35. 35.
    Braciale TJ, Sun J, Kim TS. (2012) Regulating the adaptive immune response to respiratory virus infection. Nat. Rev. Immunol. 12:295–305.CrossRefGoogle Scholar
  36. 37.
    Busse WW, Lemanske RF Jr, Gern JE. (2010) Role of viral respiratory infections in asthma and asthma exacerbations. Lancet. 376:826–34.CrossRefGoogle Scholar
  37. 38.
    Bals R, Hiemstra PS. (2004) Innate immunity in the lung: how epithelial cells fight against respiratory pathogens. Eur. Respir. J. 23:327–333.CrossRefGoogle Scholar
  38. 39.
    Hor S, et al. (2004) The T-cell lymphokine interleukin-26 targets epithelial cells through the interleukin-20 receptor 1 and interleukin-10 receptor 2 chains. J. Biol. Chem. 279:33343–33351.CrossRefGoogle Scholar
  39. 40.
    Hayden MS, Ghosh S. (2008) Shared principles in NF-kappaB signaling. Cell. 132:344–62.CrossRefGoogle Scholar
  40. 41.
    Dev A, Iyer S, Razani B, Cheng G. (2011) NF-kappaB and innate immunity. Curr. Top. Microbiol. Immunol. 349:115–43.PubMedGoogle Scholar
  41. 42.
    Liang Y, Zhou Y, Shen P. (2004) NF-kappaB and its regulation on the immune system. Cell. Mol. Immunol. 1:343–50.PubMedGoogle Scholar
  42. 43.
    Baltimore D. (2011) NF-kappaB is 25. Nat. Immunol 12:683–85.CrossRefGoogle Scholar
  43. 44.
    Zhang W, Liu HT. (2002) MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 12:9–18.CrossRefGoogle Scholar
  44. 45.
    de Sousa Abreu R, Penalva LO, Marcotte EM, Vogel C. (2009) Global signatures of protein and mRNA expression levels. Mol. Biosyst. 5:1512–26.PubMedGoogle Scholar
  45. 46.
    Toy D, et al. (2006) Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J. Immunol. 177:36–9.CrossRefGoogle Scholar
  46. 47.
    Ouyang W, Valdez P. (2008) IL-22 in mucosal immunity. Mucosal Immunol. 1:335–8.CrossRefGoogle Scholar
  47. 48.
    Wolk K, Witte E, Witte K, Warszawska K, Sabat R. (2010) Biology of interleukin-22. Semin. Immunopathol. 32:17–31.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2017

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (

Authors and Affiliations

  • Karlhans Fru Che
    • 1
  • Riitta Kaarteenaho
    • 2
  • Elisa Lappi-Blanco
    • 3
  • Bettina Levänen
    • 1
  • Jitong Sun
    • 1
  • Åsa Wheelock
    • 4
  • Lena Palmberg
    • 1
  • C. Magnus Sköld
    • 4
    • 5
  • Anders Lindén
    • 1
    • 5
  1. 1.Unit for Lung and Airway Research, Institute of Environmental MedicineKarolinska InstitutetStockholmSweden
  2. 2.Unit of Medicine and Clinical Research, Pulmonary Division, University of Eastern Finland and Center of Medicine and Clinical Research, Division of Respiratory MedicineKuopio University HospitalKuopioFinland
  3. 3.Department of Pathology, Center for Cancer Research and Translational MedicineUniversity of OuluOuluFinland
  4. 4.Respiratory Medicine Unit. Center for Molecular Medicine, Department of Medicine SolnaKarolinska InstitutetStockholmSweden
  5. 5.Lung Allergy ClinicKarolinska University Hospital SolnaStockholmSweden

Personalised recommendations