p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma

J Allergy Clin Immunol. 2002 Apr;109(4):649-57. doi: 10.1067/mai.2002.122465.


Background: Although glucocorticoids are the most effective treatment for chronic inflammatory diseases, such as asthma, some patients show a poor response. IL-2 combined with IL-4 can alter glucocorticoid receptor (GR) ligand-binding affinity and modulate glucocorticoid function.

Objective: We sought to confirm the altered ligand-binding affinity in a distinct group of steroid-dependent asthmatic subjects and examine the mechanism by which IL-2 and IL-4 modify the ligand-binding affinity of the GR.

Methods: We examined PBMCs from healthy subjects, subjects with mild asthma, and steroid-dependent subjects with severe asthma using dexamethasone-binding assays and Western blot analysis of GR and phosphorylated activated transcription factor 2 expression. GR phosphorylation was measured after orthophosphate labeling and immunoprecipitation and cytokine production by means of ELISA.

Results: GR ligand-binding affinity was reduced in the nucleus but not in the cytoplasm of steroid-dependent asthmatic subjects compared with that seen in healthy subjects (dissociation constant, 39.8 +/- 4.6 vs. 6.79 +/- 0.8 nmol/L). This difference in ligand-binding affinity could be mimicked by IL-2 and IL-4 cotreatment and was blocked by the p38 mitogen-activated kinase (MAPK) inhibitor SB203580. Activation of p38 MAPK by IL-2 and IL-4, as shown by means of phosphorylation of activated transcription factor 2, resulted in GR phosphorylation and reduced dexamethasone repression of LPS-stimulated GM-CSF release. p38 MAPK phosphorylation of CD2(+) T cells occurred on serine residues. The ability of dexamethasone to modulate IL-10 release was also inhibited by IL-2 and IL-4 cotreatment. These effects were also inhibited by SB203580.

Conclusion: These data show that p38 MAPK inhibitors may have potential in reversing glucocorticoid insensitivity and reestablishing the beneficial effects of glucocorticoids in patients with severe asthma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Asthma / drug therapy*
  • Asthma / physiopathology
  • Drug Resistance
  • Female
  • Forced Expiratory Volume
  • Glucocorticoids / therapeutic use*
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-10 / metabolism
  • Interleukin-2 / pharmacology
  • Interleukin-4 / pharmacology
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinases / physiology*
  • Phosphorylation
  • Pyridines / pharmacology
  • Receptors, Glucocorticoid / metabolism*
  • p38 Mitogen-Activated Protein Kinases


  • Glucocorticoids
  • Imidazoles
  • Interleukin-2
  • Pyridines
  • Receptors, Glucocorticoid
  • Interleukin-10
  • Interleukin-4
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580