Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes

J Clin Invest. 1998 Dec 15;102(12):2156-64. doi: 10.1172/JCI2680.


Unstimulated peripheral blood mononuclear cells (PBMCs) from corticosteroid-resistant (CR) but not corticosteroid-sensitive (CS) asthmatics demonstrate increased activating peptide-1 (AP-1)- and decreased glucocorticoid receptor (GR)-DNA binding. We test whether these abnormalities are associated with excessive generation of c-fos, the inducible component of AP-1. The c-fos transcription rate, mRNA and protein levels, and GR-DNA binding were quantitated in PBMCs, T cells, and monocytes from CS, CR, and nonasthmatic subjects. There was a 1.7-, 4.2-, and 2.3-fold greater increase in the baseline c-fos transcription rate, mRNA expression, and protein levels, respectively, in PBMCs derived from CR compared with CS patients. At optimal stimulation with PMA, there was a 5.7-, 3.4-, and 2-fold greater increase in the c-fos transcription rate, mRNA accumulation, and protein levels, respectively, in CR compared with CS PBMCs. These abnormalities were detected in both the T cell and monocyte subpopulations. PMA stimulation converted PBMCs from a CS to a CR phenotype and was associated with direct interaction between c-Fos and the GR. Pretreatment of PBMCs from CR patients with c-fos antisense oligonucleotides enhanced GR-DNA binding activity in CR PBMCs stimulated with dexamethasone. We suggest that increased c-fos synthesis provides a major mechanism for the increased AP-1- and decreased GR- DNA binding seen in CR asthma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / pharmacology*
  • Asthma / genetics*
  • DNA-Binding Proteins / genetics
  • Drug Resistance / physiology*
  • Female
  • Gene Expression / genetics
  • Genes, fos / genetics*
  • Humans
  • Inflammation / metabolism
  • Male
  • Middle Aged
  • Proto-Oncogene Proteins c-fos / genetics
  • RNA, Messenger / genetics
  • Receptors, Glucocorticoid / metabolism
  • Regulatory Sequences, Nucleic Acid / genetics
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factor AP-1 / genetics


  • Adrenal Cortex Hormones
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Transcription Factor AP-1
  • Tetradecanoylphorbol Acetate