European Cytokine Network

, Volume 28, Issue 1, pp 8–18 | Cite as

Increased serum IL-17A and Th2 cytokine levels in patients with severe uncontrolled asthma

  • Takehiro Hasegawa
  • Hitoshi Uga
  • Akio Mori
  • Hirokazu Kurata
Research Article



Asthma is a syndrome of chronic bronchial inflammation and airway remodelling. Initially, asthma has been categorized into atopic and nonatopic types, based on antigen-specific IgE levels. Moreover, recently, asthma has been classified into different endotypes based on its pathophysiology, leading to the selection of the most optimal and effective therapies. Although T helper cell type 2 (Th2) cytokines were proven to play critical roles in atopic asthma, IL-17A has been reported to be involved in severe refractory asthma.

Patients and methods

In this study, we measured the levels of 24 cytokines/chemokines in the sera of healthy controls (HCs) (n = 34) and patients with asthma (n = 77), that were compared among patient groups with different disease activities and characteristics.


The serum levels of nine cytokines were significantly higher in patients with asthma than in HCs, and the levels of IL-17A and SCF were significantly different between uncontrolled and well-controlled patient groups (p = 0.003). The IL-17A levels were significantly correlated with those of IL-4, IL-25, IL-10, and IFN-γ in patients with uncontrolled asthma, and the patients with the highest levels of all the above cytokines were refractory to high-dose of inhaled corticosteroid therapy and have a history of acute exacerbation within 1 year, requiring systemic steroid therapy.


This study examines the profiles of upregulation and downregulation of various cytokines and chemokines in relation to asthmatic control status. IL-17A was significantly upregulated in patients with the uncontrolled and refractory status. Therefore, IL-17A may play important roles in asthmatic exacerbation, and its high level, in combination with upregulated Th2 and other cytokines, may indicate the refractory endotype of asthma.

Key words

asthma endotype uncontrolled asthma serum cytokines IL-17 Th2 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012; 18: 716–25.CrossRefPubMedGoogle Scholar
  2. 2.
    Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008; 178: 218–24.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lotvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011; 127: 355–60.CrossRefPubMedGoogle Scholar
  4. 4.
    Szefler SJ, Wenzel S, Brown R, et al. Asthma outcomes: biomarkers. J Allergy Clin Immunol 2012; 129: S9–23.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hanania NA, Wenzel S, Rosen K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 2013; 187: 804–11.CrossRefPubMedGoogle Scholar
  6. 6.
    Bjermer L, Alving K, Diamant Z, et al. Current evidence and future research needs for FeNO measurement in respiratory diseases. Respir Med 2014; 108: 830–41.CrossRefPubMedGoogle Scholar
  7. 7.
    Trevor JL, Deshane JS. Refractory asthma: mechanisms, targets, and therapy. Allergy 2014; 69: 817–27.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Pukelsheim K, Stoeger T, Kutschke D, Ganguly K, Wjst M. Cytokine profiles in asthma families depend on age and phenotype. PLoS One 2010; 5: e14299.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bettiol J, Sele J, Henket M, et al. Cytokine production from sputum cells after allergenic challenge in IgE-mediated asthma. Allergy 2002; 57: 1145–50.CrossRefPubMedGoogle Scholar
  10. 10.
    Wong CK, Ho CY, Ko FW, et al. Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-gamma, IL-4, IL-10 and IL-13) in patients with allergic asthma. Clin Exp Immunol 2001; 125: 177–83.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Fahy JV. Type 2 inflammation in asthma–present in most, absent in many. Nat Rev Immunol 2015; 15: 57–65.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lloyd CM, Hessel EM. Functions of T cells in asthma: more than just T(H)2 cells. Nat Rev Immunol 2010; 10: 838–48.CrossRefPubMedGoogle Scholar
  13. 13.
    Souwer Y, Szegedi K, Kapsenberg ML, de Jong EC. IL-17 and IL-22 in atopic allergic disease. Curr Opin Immunol 2010; 22: 821–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Ciprandi G, De Amici M, Murdaca G, et al. Serum interleukin-17 levels are related to clinical severity in allergic rhinitis. Allergy 2009; 64: 1375–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Agache I, Ciobanu C, Agache C, Anghel M. Increased serum IL-17 is an independent risk factor for severe asthma. Respir Med 2010; 104: 1131–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Doe C, Bafadhel M, Siddiqui S, et al. Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD. Chest 2010; 138: 1140–7.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wang YH, Wills-Karp M. The potential role of interleukin-17 in severe asthma. Curr Allergy Asthma Rep 2011; 11: 388–94.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Newcomb DC, Peebles Jr. RS. Th17-mediated inflammation in asthma. Curr Opin Immunol 2013; 25: 755–60.CrossRefPubMedGoogle Scholar
  19. 19.
    Chesne J, Braza F, Mahay G, Brouard S, Aronica M, Magnan A. IL-17 in severe asthma. Where do we stand? Am J Respir Crit Care Med 2014; 190: 1094–101.CrossRefPubMedGoogle Scholar
  20. 20.
    Chambers ES, Nanzer AM, Pfeffer PE, et al. Distinct endotypes of steroid-resistant asthma characterized by IL-17A(high) and IFNgamma( high) immunophenotypes: potential benefits of calcitriol. J Allergy Clin Immunol 2015; 138: 628–37.CrossRefGoogle Scholar
  21. 21.
    Wilson RH, Whitehead GS, Nakano H, Free ME, Kolls JK, Cook DN. Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness. Am J Respir Crit Care Med 2009; 180: 720–30.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wakashin H, Hirose K, Maezawa Y, et al. IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway inflammation in mice. Am J Respir Crit Care Med 2008; 178: 1023–32.CrossRefPubMedGoogle Scholar
  23. 23.
    Alyasin S, Karimi MH, Amin R, Babaei M, Darougar S. Interleukin-17 gene expression and serum levels in children with severe asthma. Iran J Immunol 2013; 10: 177–85.PubMedGoogle Scholar
  24. 24.
    Zhou X, Fragala MS, McElhaney JE, Kuchel GA. Conceptual and methodological issues relevant to cytokine and inflammatory marker measurements in clinical research. Curr Opin Clin Nutr Metab Care 2010; 13: 541–7.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sullivan KE, Cutilli J, Piliero LM, et al. Measurement of cytokine secretion, intracellular protein expression, and mRNA in resting and stimulated peripheral blood mononuclear cells. Clin Diagn Lab Immunol 2000; 7: 920–4.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Bienvenu J, Monneret G, Fabien N, Revillard JP. The clinical usefulness of the measurement of cytokines. Clin Chem Lab Med 2000; 38: 267–85.CrossRefPubMedGoogle Scholar
  27. 27.
    Rabinowitz J, Petros WP, Stuart AR, Peters WP. Characterization of endogenous cytokine concentrations after high-dose chemotherapy with autologous bone marrow support. Blood 1993; 81: 2452–9.PubMedGoogle Scholar
  28. 28.
    Abbal C, Persi L, Bousquet J, Yssel H, Pene J. Effect of bronchial allergen challenge on in vitro cytokine release by peripheral blood mononuclear cells of atopic patients. Allergy 1998; 53: 945–50.CrossRefPubMedGoogle Scholar
  29. 29.
    Liang Z, Liu L, Zhao H, et al. A systemic inflammatory endotype of asthma with more severe disease identified by unbiased clustering of the serum cytokine profile. Medicine 2016; 95: e3774.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol 2015; 16: 45–56.CrossRefPubMedGoogle Scholar
  31. 31.
    Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010; 181: 315–23.CrossRefPubMedGoogle Scholar
  32. 32.
    Siroux V, Basagana X, Boudier A, et al. Identifying adult asthma phenotypes using a clustering approach. Eur Respir J 2011; 38: 310–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009; 180: 388–95.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Vazquez-Tello A, Halwani R, Hamid Q, Al-Muhsen S. Glucocorticoid receptor-beta up-regulation and steroid resistance induction by IL-17 and IL-23 cytokine stimulation in peripheral mononuclear cells. J Clin Immunol 2013; 33: 466–78.CrossRefPubMedGoogle Scholar
  35. 35.
    Zijlstra GJ, Ten Hacken NH, Hoffmann RF, van Oosterhout AJ, Heijink IH. Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells. Eur Respir J 2012; 39: 439–45.CrossRefPubMedGoogle Scholar
  36. 36.
    Chakir J, Shannon J, Molet S, et al. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGFbeta, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol 2003; 111: 1293–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Nanzer AM, Chambers ES, Ryanna K, et al. Enhanced production of IL-17A in patients with severe asthma is inhibited by 1alpha,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion. J Allergy Clin Immunol 2013; 132: 297–304.CrossRefPubMedGoogle Scholar
  38. 38.
    Al-Ramli W, Al Samri M, Hamid Q. Th-17 cell-related cytokines’ potential role in the pathogenesis of severe asthma. J Asthma 2008; 45: 41–4.CrossRefPubMedGoogle Scholar
  39. 39.
    Kim HY, Lee HJ, Chang YJ, et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesityassociated airway hyperreactivity. Nat Med 2014; 20: 54–61.CrossRefPubMedGoogle Scholar
  40. 40.
    Irvin C, Zafar I, Good J, et al. Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J Allergy Clin Immunol 2014; 134: 1175–86.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Choy DF, Hart KM, Borthwick LA, et al. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci Transl Med 2015; 7: 301ra129.CrossRefPubMedGoogle Scholar
  42. 42.
    Cosmi L, Liotta F, Maggi E, Romagnani S, Annunziato F. Th17 cells: new players in asthma pathogenesis. Allergy 2011; 66: 989–98.CrossRefPubMedGoogle Scholar
  43. 43.
    Wang YH, Voo KS, Liu B, et al. A novel subset of CD4(+) T(H)2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma. J Exp Med 2010; 207: 2479–91.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Peters MC, Mekonnen ZK, Yuan S, Bhakta NR, Woodruff PG, Fahy JV. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol 2014; 133: 388–94.CrossRefPubMedGoogle Scholar
  45. 45.
    Seys SF, Grabowski M, Adriaensen W, et al. Sputum cytokine mapping reveals an ‘IL-5, IL-17A, IL-25-high’ pattern associated with poorly controlled asthma. Clin Exp Allergy 2013; 43: 1009–17.CrossRefPubMedGoogle Scholar
  46. 46.
    Cheng D, Xue Z, Yi L, et al. Epithelial interleukin-25 is a key mediator in Th2-high, corticosteroid-responsive asthma. Am J Respir Crit Care Med 2014; 190: 639–48.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Zhao Y, Yang J, Gao YD, Guo W. Th17 immunity in patients with allergic asthma. Int Arch Allergy Immunol 2010; 151: 297–307.CrossRefPubMedGoogle Scholar
  48. 48.
    Kinyanjui MW, Shan J, Nakada EM, Qureshi ST, Fixman ED. Dose-dependent effects of IL-17 on IL-13-induced airway inflammatory responses and airway hyperresponsiveness. J Immunol 2013; 190: 3859–68.CrossRefPubMedGoogle Scholar
  49. 49.
    Barlow JL, Flynn RJ, Ballantyne SJ, McKenzie AN. Reciprocal expression of IL-25 and IL-17A is important for allergic airways hyperreactivity. Clin Exp Allergy 2011; 41: 1447–55.CrossRefPubMedGoogle Scholar
  50. 50.
    Mizutani N, Nabe T, Yoshino S. IL-17A promotes the exacerbation of IL-33-induced airway hyperresponsiveness by enhancing neutrophilic inflammation via CXCR2 signaling in mice. J Immunol 2014; 192: 1372–84.CrossRefPubMedGoogle Scholar
  51. 51.
    Ji X, Li J, Xu L, et al. IL4 and IL-17A provide a Th2/Th17-polarized inflammatory milieu in favor of TGF-beta1 to induce bronchial epithelial-mesenchymal transition (EMT). Int J Clin Exp Pathol 2013; 6: 1481–92.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Shannon J, Ernst P, Yamauchi Y, et al. Differences in airway cytokine profile in severe asthma compared to moderate asthma. Chest 2008; 133: 420–6.CrossRefPubMedGoogle Scholar
  53. 53.
    Liu L, Jarjour NN, Busse WW, Kelly EA. Enhanced generation of helper T type 1 and 2 chemokines in allergen-induced asthma. Am J Respir Crit Care Med 2004; 169: 1118–24.CrossRefPubMedGoogle Scholar
  54. 54.
    Saraiva M, O’Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010; 10: 170–81.CrossRefPubMedGoogle Scholar
  55. 55.
    Koponen P, Nuolivirta K, Virta M, Helminen M, Hurme M, Korppi M. Polymorphism of the rs1800896 IL10 promoter gene protects children from post-bronchiolitis asthma. Pediatr Pulmonol 2014; 49: 800–6.CrossRefPubMedGoogle Scholar
  56. 56.
    Ghannam S, Pene J, Moquet-Torcy G, Jorgensen C, Yssel H. Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol 2010; 185: 302–12.CrossRefPubMedGoogle Scholar
  57. 57.
    Zhang YL, Luan B, Wang XF, et al. Peripheral blood MDSCs, IL-10 and IL-12 in children with asthma and their importance in asthma development. PLoS One 2013; 8: e63775.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Raeiszadeh Jahromi S, Mahesh PA, Jayaraj BS, et al. Serum levels of IL-10, IL-17F and IL-33 in patients with asthma: a case-control study. J Asthma 2014; 51: 1004–13.CrossRefPubMedGoogle Scholar
  59. 59.
    Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 2008; 372: 1107–19.CrossRefPubMedGoogle Scholar
  60. 60.
    Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360: 973–84.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© John Libbey Eurotext 2017

Authors and Affiliations

  • Takehiro Hasegawa
    • 1
    • 2
  • Hitoshi Uga
    • 1
  • Akio Mori
    • 3
  • Hirokazu Kurata
    • 1
    • 2
  1. 1.Sysmex CorporationKobeJapan
  2. 2.Division of System Biology of Disease, Department of Internal RelatedKobe University Graduate School of MedicineKobeJapan
  3. 3.Clinical Research Center for Allergy and RheumatologySagamihara National HospitalSagamiharaJapan

Personalised recommendations