title: Synthetic response of stimulated respiratory epithelium: modulation by prednisolone and iKK2 inhibition.
abstract: BACKGROUND
  The airway epithelium plays a central role in wound repair and host defense and is implicated in the immunopathogenesis of asthma. Whether there are intrinsic differences between the synthetic capacity of epithelial cells derived from subjects with asthma and healthy control subjects and how this mediator release is modulated by antiinflammatory therapy remains uncertain. We sought to examine the synthetic function of epithelial cells from different locations in the airway tree from subjects with and without asthma and to determine the effects of antiinflammatory therapies upon this synthetic capacity.
  
  
  METHODS
  Primary epithelial cells were derived from 17 subjects with asthma and 16 control subjects. The release of 13 cytokines and chemokines from nasal, bronchial basal, and air-liquid interface differentiated epithelial cells before and after stimulation with IL-1β, IL-1β and interferon-γ, or Poly-IC (Toll-like receptor 3 agonist) was measured using MesoScale discovery or enzyme-linked immunosorbent assay, and the effects of prednisolone and an inhibitor of nuclear factor κ-B2 (IKK2i) were determined.
  
  
  RESULTS
  The pattern of release of cytokines and chemokines was significantly different between nasal, bronchial basal, and differentiated epithelial cells but not between health and disease. Stimulation of the epithelial cells caused marked upregulation of most mediators, which were broadly corticosteroid unresponsive but attenuated by IKK2i.
  
  
  CONCLUSIONS
  Synthetic capacity of primary airway epithelial cells varied between location and degree of differentiation but was not disease specific. Activation of epithelial cells by proinflammatory cytokines and toll-like receptor 3 agonism is attenuated by IKK2i, but not corticosteroids, suggesting that IKK2i may represent an important novel therapy for asthma.
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester and Department of Respiratory Medicine, Glenfield Hospital, Leicester, England.
authors.forename: Lucy Bianca
authors.initials: LB
authors.lastname: Woodman
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester and Department of Respiratory Medicine, Glenfield Hospital, Leicester, England.
authors.forename: Wing Yan Heidi
authors.initials: WYH
authors.lastname: Wan
authors.affiliation: GlaxoSmithKline, Refractory Respiratory Inflammation DPU, Respiratory CEDD Biomarker Discovery Group, Stevenage, England.
authors.forename: Roberta
authors.initials: R
authors.lastname: Milone
authors.affiliation: GlaxoSmithKline, Refractory Respiratory Inflammation DPU, Respiratory CEDD Biomarker Discovery Group, Stevenage, England.
authors.forename: Ken
authors.initials: K
authors.lastname: Grace
authors.affiliation: GlaxoSmithKline, Refractory Respiratory Inflammation DPU, Respiratory CEDD Biomarker Discovery Group, Stevenage, England.
authors.forename: Ana
authors.initials: A
authors.lastname: Sousa
authors.affiliation: GlaxoSmithKline, Refractory Respiratory Inflammation DPU, Respiratory CEDD Biomarker Discovery Group, Stevenage, England.
authors.forename: Rick
authors.initials: R
authors.lastname: Williamson
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester and Department of Respiratory Medicine, Glenfield Hospital, Leicester, England. Electronic address: ceb17@le.ac.uk.
authors.forename: Christopher Edward
authors.initials: CE
authors.lastname: Brightling
mesh_terms: D000704:Analysis of Variance; D001249:Asthma / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D020672:I-kappa B Proteins / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D011239:Prednisolone / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018925:Chemokines; D016207:Cytokines; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D011239:Prednisolone; D051550:I-kappa B Kinase