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

Unstimulated peripheral blood mononuclear cells (PBMCs) from corticosteroid -resistant (CR) but not corticosteroid-sensitive (CS) asthmatics demonstrat e increased activating peptide-1 (AP-1)- and decreased glucocorticoid recep tor (GR)-DNA binding, We test whether these abnormalities are associated wi th excessive generation of c-fos, the inducible component of AP-1., The c-f os transcription rate, mRNA and protein levels, and GR-DNA binding were qua ntitated in PBMCs, T cells, and monocytes from CS, CR, and nonasthmatic sub jects. There was a 1.7-, 4.2-, and 2.3-fold greater increase in the baselin e c-fos transcription rate, mRNA expression, and protein levels, respective ly, in PBMCs derived from CR compared with CS patients. At optimal stimulat ion 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 t he 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 antisen se oligonucleotides enhanced GR-DNA binding activity in CR PBMCs stimulated with dexamethasone, We suggest that increased c-fos synthesis provides a m ajor mechanism for the increased AP-1- and decreased GR-DNA binding seen in CR asthma.