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

J Allergy Clin Immunol. 1999 Sep;104(3 Pt 1):565-74. doi: 10.1016/s0091-6749(99)70325-8.

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).

Conclusion: 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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / therapeutic use*
  • Asthma / drug therapy*
  • Asthma / metabolism
  • Double-Blind Method
  • Drug Resistance
  • Female
  • Glucocorticoids / therapeutic use*
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Male
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Prednisolone / therapeutic use*
  • Proto-Oncogene Proteins c-fos / biosynthesis
  • Proto-Oncogene Proteins c-jun / biosynthesis
  • Transcription Factor AP-1 / metabolism*

Substances

  • Anti-Inflammatory Agents
  • Glucocorticoids
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Transcription Factor AP-1
  • Prednisolone
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases