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 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.
Lane
S J
SJ
Departments of Respiratory Medicine and Allergy, Guy's Hospital, London SE1 9RT, United Kingdom.
Adcock
I M
IM
Richards
D
D
Hawrylowicz
C
C
Barnes
P J
PJ
Lee
T H
TH
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D001249:Asthma / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004351:Drug Resistance / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D016762:Genes, fos / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics
D000305:Adrenal Cortex Hormones; D004268:DNA-Binding Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D013755:Tetradecanoylphorbol Acetate