Induction of glucocorticoid receptor-beta expression in epithelial cells of asthmatic airways by T-helper type 17 cytokines.
BACKGROUND
Corticosteroid insensitivity in asthmatics is associated with an increased expression of glucocorticoid receptor-beta (GR-beta) in many cell types. T-helper type 17 (Th17) cytokine (IL-17A and F) expressions increase in mild and in difficult-to-treat asthma. We hypothesize that IL-17A and F cytokines alone or in combination, induce the expression of GR-beta in bronchial epithelial cells.


OBJECTIVE
To confirm the expression of the GR-beta and IL-17 cytokines in the airways of normal subjects and mild asthmatics and to examine the effect of cytokines IL-17A and F on the expression of GR-beta in bronchial epithelial cells obtained from normal subjects and asthmatic patients.


METHODS
The expression of IL-17A and F, GR-alpha and GR-beta was analysed in bronchial biopsies from mild asthmatics and normal subjects by Q-RT-PCR. Immunohistochemistry for IL-17 and GR-beta was performed in bronchial biopsies from normal and asthmatic subjects. The expression of IL-6 in response to IL-17A and F and dexamethasone was determined by Q-RT-PCR using primary airway epithelial cells from normal and asthmatic subjects.


RESULTS
We detected significantly higher levels of IL-17A mRNA expression in the bronchial biopsies from mild asthmatics, compared with normal. GR-alpha expression was significantly lower in the biopsies from asthmatics compared with controls. The expression of IL-17F and GR-beta in biopsies from asthmatics was not significantly different from that of controls. Using primary epithelial cells isolated from normal subjects and asthmatics, we found an increased expression of GR-beta in response to IL-17A and F in the cells from asthmatics (P< or =0.05). This effect was only partially significant in the normal cells. Dexamethasone significantly decreased the IL-17-induced IL-6 expression in cells from normal individuals but not in those from asthmatics (P< or =0.05).


CONCLUSIONS
Evidence of an increased GR-beta expression in epithelial cells following IL-17 stimulation suggests a possible role for Th17-associated cytokines in the mechanism of steroid hypo-responsiveness in asthmatic subjects.
Vazquez-Tello
A
A
Meakins-Christie Laboratories, Department of Medicine, Respiratory Division, McGill University, 3626 St. Urbain Street, Montreal, QC, Canada.
Semlali
A
A
Chakir
J
J
Martin
J G
JG
Leung
D Y
DY
Eidelman
D H
DH
Hamid
Q
Q
D000328:Adult; D001249:Asthma / Q000276:immunology*; D001980:Bronchi / Q000276:immunology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
D020381:Interleukin-17; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta; D003907:Dexamethasone