Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling.
BACKGROUND
Increased airway smooth muscle bulk is a pathological feature of asthma. Asthma is well controlled by the combined inhalation of glucocorticoids and beta2-adrenoceptor agonists. The basic molecular mechanism of the interaction of the two drugs on proliferation of airway smooth muscle cells is yet to be identified. Our aim was to elucidate how glucocorticoids and beta2 agonists affect the growth of human bronchial airway smooth muscle cells.


METHODS
We assessed the effect of formoterol and budesonide on the activation and function of transcription factors by immunohistochemistry, western blotting, DNA mobility shift assay, and a luciferase reporter gene assay. The effect of the drugs and the involvement of specific transcription factors on cell proliferation was ascertained by direct cell count and confirmed by thymidine incorporation.


RESULTS
Both classes of drugs (10(-8) mol/L) activated C/EBP-alpha and the glucocorticoid receptor with different kinetic profiles, and inhibited proliferation. The combination of lower doses of drugs (10(-12) to 10(-9) mol/L) resulted in a synchronised activation of the transcription factors and an enhanced antiproliferative effect. The action of the drugs alone or in combination on transcription-factor activity and proliferation was suppressed by either depletion of C/EBP-alpha or in the presence of a glucocorticoid-receptor blocker.


CONCLUSIONS
Our findings could provide one explanation for the interaction of beta2 agonists and glucocorticoids at a molecular level, and indicate that the concentration of inhaled glucocorticoids can be reduced when combined with beta2 agonists, minimising the side-effects of the drugs.
Roth
Michael
M
Department of Pharmacology and The Woolcock Institute of Medical Research, University of Sydney, NSW 2006, Australia. michaelr@mail.med.usyd.edu.au
Johnson
Peter R A
PR
Rüdiger
Jochen J
JJ
King
Gregory G
GG
Ge
Qi
Q
Burgess
Janette K
JK
Anderson
Gary
G
Tamm
Michael
M
Black
Judith L
JL
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D001249:Asthma / Q000178:diet therapy; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology* / Q000187:drug effects; D019819:Budesonide / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004347:Drug Interactions; D004983:Ethanolamines / Q000494:pharmacology; D000068759:Formoterol Fumarate; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects; D014157:Transcription Factors / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D005938:Glucocorticoids; D014157:Transcription Factors; D019819:Budesonide; D000068759:Formoterol Fumarate