Asthma and lower airway disease
Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

https://doi.org/10.1016/j.jaci.2013.03.037Get rights and content

Background

TH17 cells are proposed to play a role in the pathology of asthma, including steroid-resistant (SR) disease. We previously identified a steroid-enhancing function of vitamin D in patients with SR asthma in restoring the impaired response to steroids for production of the anti-inflammatory cytokine IL-10.

Objective

We sought to investigate the production of the TH17-associated cytokines IL-17A and IL-22 in culture in patients with moderate-to-severe asthma defined on the basis of their clinical response to steroids and the susceptibility of this response to inhibition by steroids and the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25[OH]2D3).

Methods

PBMCs were stimulated in culture with or without dexamethasone and 1,25(OH)2D3. A cytometric bead array, ELISA, and intracellular cytokine staining were used to assess cytokine production. The role of CD39 in inhibition of the TH17 response was studied by using quantitative real-time PCR, flow cytometry, and addition of the antagonist POM-1 to culture.

Results

Asthmatic patients synthesized much higher levels of IL-17A and IL-22 than nonasthmatic control subjects, with patients with SR asthma expressing the highest levels of IL-17A. Glucocorticoids did not inhibit IL-17A cytokine expression in patients and enhanced production in cultures from control subjects. Treatment with 1,25(OH)2D3 with or without dexamethasone significantly reduced both IL-17A and IL-22 levels. An antagonist of the ectonucleotidase CD39 reversed 1,25(OH)2D3-mediated inhibition of the IL-17A response.

Conclusion

Patients with severe asthma exhibit increased levels of TH17 cytokines, which are not inhibited by steroids. 1,25(OH)2D3 inhibits TH17 cytokine production in all patients studied, irrespective of their clinical responsiveness to steroids, identifying novel steroid-enhancing properties of vitamin D in asthmatic patients.

Section snippets

Subjects

Healthy adults (study approved by the local research ethics committee, 09/H0804/77) and asthmatic patients (08/H0804/84) were recruited. All healthy control subjects and patients provided written informed consent. Asthmatic patients had moderate-to-severe asthma for at least 6 months on therapy step 3 or 4 of the British Thoracic Society guidelines on the management of asthma diagnosed by a specialist physician. The average inhaled corticosteroid dose in beclomethasone diproprionate equivalents

Comparison of IL-17A and IL-22 production by PBMCs in culture from patients with SS and patients with SR asthma

Details of the 2 cohorts of patients with moderate-to-severe asthma, defined as SS or SR asthma on the basis of changes in lung function after a 2-week course of oral prednisolone, and of healthy nonasthmatic control subjects are provided in the Methods section. Notably, these 2 patient groups exhibited comparable disease severity based on impairment of lung function and were taking comparable doses of inhaled corticosteroids (total dosages based on beclomethasone dipropionate equivalence).

Discussion

Our data demonstrate that the production of IL-17A and IL-22 by human peripheral blood CD4+ T cells is increased in patients with severe asthma. Notably, IL-17A levels, but not IL-22 levels, were approximately 5-fold greater in patients with SR asthma compared with those seen in patients with SS asthma. Strikingly, the glucocorticoid dexamethasone significantly enhanced the frequency of IL-17A+ cells in culture in both nonasthmatic control subjects and asthmatic patients, although IL-17A

References (49)

  • J. Chakir et al.

    Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression

    J Allergy Clin Immunol

    (2003)
  • S.E. Wenzel

    Asthma phenotypes: the evolution from clinical to molecular approaches

    Nat Med

    (2012)
  • N.R. Bhakta et al.

    Human asthma phenotypes: from the clinic, to cytokines, and back again

    Immunol Rev

    (2011)
  • K.F. Chung et al.

    Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma

    Eur Respir J

    (1999)
  • A. Bush et al.

    WHO universal definition of severe asthma

    Curr Opin Allergy Clin Immunol

    (2011)
  • C.J. Corrigan

    Asthma refractory to glucocorticoids: the role of newer immunosuppressants

    Am J Respir Med

    (2002)
  • I.M. Adcock et al.

    Steroid resistance in asthma: mechanisms and treatment options

    Curr Allergy Asthma Rep

    (2008)
  • P. Bhavsar et al.

    Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma

    Thorax

    (2008)
  • J. Mogil

    Many asthma patients experience persistent symptoms despite appropriate clinical and guideline-based treatment with inhaled corticosteroids

    J Am Acad Nurse Pract

    (2007)
  • W. Huang et al.

    Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice

    J Infect Dis

    (2004)
  • K.I. Happel et al.

    Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae

    J Exp Med

    (2005)
  • D.J. Cua et al.

    Innate IL-17-producing cells: the sentinels of the immune system

    Nat Rev Immunol

    (2010)
  • P. Ye et al.

    Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense

    J Exp Med

    (2001)
  • D.M. Bullens et al.

    IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx?

    Respir Res

    (2006)
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    Supported by Asthma UK through project grants 08/040 and 11/040. A.M.N. is funded by Asthma UK. E.S.C. is funded by an MRC British Thoracic Society/Morriston Davies Trust Capacity Building PhD Studentship. K.R. was in receipt of an MRC Clinical Training Research Fellowship. The research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.

    Disclosure of potential conflict of interest: E. S. Chambers has received an MRC Centenary Award and has received a BSI International Travel Grant. K. Ryanna has received an MRC Clinical Research Training Fellowship. C. J. Corrigan has received honoraria for consultancy from Meda and from Chiesi, has received one or more grants from or has one or more grants pending with and has received one or more payments for travel/accommodations/meeting expenses from Novartis, and has received honoraria for lectures from Allergy Therapeutics. C. M. Hawrylowicz has been supported by one or more grants from Asthma UK and has received an Ancillary grant from the National Institutes of Health, a Wellcome Trust Clinical Research Training Fellowship, and MRC PhD studentships. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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