title: In vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosyphorylation of JUN N-terminal kinase and failure of prednisolone to inhibit JUN N-terminal kinase phosphorylation.
abstract: BACKGROUND
  Corticosteroid-resistant (CR) asthma is associated with increased in vitro activity of the proinflammatory transcription factor activating peptide (AP)-1 in PBMCs resulting from increased c-FOS synthesis. Increased AP-1 may sequester the glucocorticoid receptor to produce a CR state. Using the tuberculin-induced inflammatory responses in the skin, we have previously demonstrated that a therapeutically effective dose of prednisolone suppressed T-cell, macrophage, and eosinophil infiltration into purified protein derivative-induced lesional skin of corticosteroid-sensitive (CS), but not CR, individuals.
  
  
  OBJECTIVE
  Skin biopsy specimens from a tuberculin-induced model of dermal inflammation have been evaluated for the effect of corticosteroids in regulating components of AP-1 in vivo.
  
  
  METHODS
  Immunohistochemical analysis of the tuberculin-mediated cutaneous response has been performed on 9 subjects with CS asthma and 6 subjects with CR asthma for the regulatory components of AP-1 before and after 9 days of either 40 mg prednisolone or placebo.
  
  
  RESULTS
  Significantly greater expression of c-FOS, phosphorylated c-JUN, and phosphorylated JUN N-terminal kinase (JNK) protein has been identified in CR than in CS subjects. Corticosteroids suppressed phosphorylation of c-JUN and JNK in the CS Group (P =.004 for both) but enhanced phosphorylation of c-JUN and JNK in the CR group (P =.031 for both).
  
  
  CONCLUSIONS
  Resistance to corticosteroids in asthmatic subjects may be caused, at least in part, by failure to suppress JNK phosphorylation, leading to failure to suppress c-JUN N-phosphorylation. Increased JNK may be one of the mechanisms central to the mechanism of CR asthma.
authors.affiliation: Department of Respiratory Medicine and Allergy, King's College, and Guy's Hospital, London, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Sousa
authors.forename: S J
authors.initials: SJ
authors.lastname: Lane
authors.forename: C
authors.initials: C
authors.lastname: Soh
authors.forename: T H
authors.initials: TH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011239:Prednisolone / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D011239:Prednisolone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases