Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling

Publication

Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling

Journal Paper/Review - Oct 26, 2002

Roth Michael, Johnson Peter R A, Rüdiger Jochen, King Gregory G, Ge Qi, Burgess Janette K, Anderson Gary, Tamm Michael, Black Judith L

Citation

Roth M, Johnson P, Rüdiger J, King G, Ge Q, Burgess J, Anderson G, Tamm M, Black J. Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling. Lancet 2002; 360:1293-9.

Type

Journal Paper/Review (English)

Journal

Lancet 2002; 360

Publication Date

Oct 26, 2002

Issn Print

0140-6736

Pages

1293-9

Brief description/objective

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.

FINDINGS
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.

INTERPRETATION
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.