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Previous Volume 351:560-574 August 5, 2004 Number 6 Next

Dysfunctional Interaction of C/EBP and the Glucocorticoid Receptor in Asthmatic Bronchial Smooth-Muscle Cells

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ABSTRACT

Background Increased proliferation of bronchial smooth-muscle cells may lead to increased muscle mass in the airways of patients with asthma. The antiproliferative effect of glucocorticoids in bronchial smooth-muscle cells in subjects without asthma is mediated by a complex of the glucocorticoid receptor and the CCAAT/enhancer binding protein (C/EBP). We examined the signaling pathway controlling the inhibitory effect of glucocorticoids on cell proliferation and interleukin-6 synthesis in bronchial smooth-muscle cells of subjects with asthma and those without asthma.

Methods Lines of bronchial smooth-muscle cells were established from cells from 20 subjects with asthma, 8 subjects with emphysema, and 26 control subjects. Cell proliferation was determined by means of cell counts and [³H]thymidine incorporation. Signal transduction was studied by means of an electrophoretic DNA mobility-shift assay, a supershift electrophoretic-mobility assay, immunoblotting, use of C/EBP antisense oligonucleotides, and use of a human C/EBP expression vector. Interleukin-6 release was determined by means of an enzyme-linked immunosorbent assay.

Results Glucocorticoids activated the glucocorticoid receptor and inhibited serum-induced secretion of interleukin-6 in bronchial smooth-muscle cells from both subjects with asthma and those without asthma; however, glucocorticoids inhibited proliferation only in bronchial smooth-muscle cells from subjects without asthma. C/EBP protein was detected by immunoblotting in all bronchial smooth-muscle cells from subjects without asthma but not in those with asthma, whereas the protein was expressed in lymphocytes from both groups of subjects. C/EBP antisense oligonucleotides or the glucocorticoid-receptor inhibitor mifepristone reversed the antiproliferative effect of glucocorticoids in bronchial smooth-muscle cells from subjects without asthma. When bronchial smooth-muscle cells from subjects with asthma were transiently transfected with an expression vector for human C/EBP, two forms of the protein were expressed, and subsequent administration of glucocorticoids inhibited cell proliferation.

Conclusions We hypothesize that a cell-type–specific absence of C/EBP is responsible for the enhanced proliferation of bronchial smooth-muscle cells derived from subjects with asthma and that it explains the failure of glucocorticoids to inhibit proliferation in vitro.

Source Information

From the Department of Pharmacology and the Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia (M.R., P.R.A.J., P.B., G.G.K., Q.G., K.H., J.K.B., J.L.B.); and the Departments of Research and Internal Medicine, Pulmonary Cell Research, University Hospitals Basel, Basel, Switzerland (M.R., M.P.B., J.J.R., M.T.).

Drs. Johnson, Borger, Black, and Tamm contributed equally to this article.

Full Text of this Article

Related Letters:

C/EBP in Asthma
Levy D. I., Roth M., Borger P., Tamm M.
Extract | Full Text | PDF  
N Engl J Med 2004; 351:2236-2237, Nov 18, 2004. Correspondence

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