Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients.
BACKGROUND
Overexpression of the transcriptional regulatory factor activator protein 1 might contribute to T-cell glucocorticoid (GC) refractoriness in GC-resistant asthma.


OBJECTIVE
We sought to address the hypothesis that clinically GC-resistant asthma is accompanied by failure of systemic GCs to inhibit phosphorylation of c-jun and c-jun N-terminal kinase (JNK) in bronchial mucosal cells.


METHODS
We performed enumeration of total (CD45+) leukocytes and cells expressing c-fos and total and phosphorylated c-jun and JNK in bronchial biopsy sections from 9 GC-sensitive and 17 GC-resistant asthmatic patients taken before and after oral prednisolone (40 mg/1.72 m(2) body surface area daily for 14 days) using specific antibodies, immunohistochemistry, and image analysis.


RESULTS
At baseline, mean total (CD45+) mucosal leukocytes, total cells expressing phosphorylated c-jun and JNK, and mean percentages of cells in which these molecules were phosphorylated were similar in both groups, whereas mean total numbers of c-fos-immunoreactive cells were increased in the GC-resistant asthmatic subjects (P = .04). After prednisolone, the mean total cells expressing phosphorylated c-jun and JNK and the mean percentages of cells in which these molecules were phosphorylated were significantly reduced in the GC-sensitive (P < or = .02) but not the GC-resistant asthmatic subjects. Mean total CD45+ leukocytes and c-fos-immunoreactive cells were not significantly altered in either group.


CONCLUSIONS
Clinical GC responsiveness in asthma is accompanied by reduced phosphorylation of bronchial mucosal c-jun and JNK, a phenomenon not seen in resistant patients.


CONCLUSIONS
Dysregulation of activator protein 1 activation leading to clinical GC resistance might reflect identifiable environmental influences and is a target for future therapy.
Loke
Tuck-Kay
TK
King's College London, MRC, London SE1 9RT.
Mallett
Kirsty H
KH
Ratoff
Jonathan
J
O'Connor
Brian J
BJ
Ying
Sun
S
Meng
Qiu
Q
Soh
Cecilia
C
Lee
Tak H
TH
Corrigan
Chris J
CJ
D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011239:Prednisolone / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D005938:Glucocorticoids; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D011239:Prednisolone; D048031:JNK Mitogen-Activated Protein Kinases; D017493:Leukocyte Common Antigens