Modulation of GM-CSF release by enantiomers of beta-agonists in human airway smooth muscle.
BACKGROUND
beta 2 -Adrenergic receptor agonists can reduce the release of GM-CSF by human airway smooth muscle cells (HASMCs). These effects are considered anti-inflammatory and are ascribed to the activity of the (R)-enantiomer within the racemate of the agonist. However, the effect of the (S)-enantiomer on GM-CSF release, once thought to be inert, has not been extensively explored. Objective We hypothesized that the (S)-enantiomer may counter the effects of the (R)-enantiomer, potentially increasing GM-CSF release. Therefore, the effects of administration of individual and combined enantiomers on GM-CSF release were examined.


METHODS
Cultured HASMCs were stimulated with IL-1beta, TNF-alpha, and IFN-gamma and treated with (R)-enantiomers and (S)-enantiomers of albuterol and formoterol, with and without propranolol and ICI-118,551, and in combination with dexamethasone. GM-CSF in the resulting conditioned media was assessed by ELISA.


RESULTS
(R)-enantiomers significantly reduced GM-CSF release by as much as 41% ( P < .05), which was reversible with propranolol. In contrast, (S)-enantiomers significantly increased GM-CSF release by as much as 34% ( P < .05) over release with no drug, and by 25% to 40% ( P < .05) when added with (R)-enantiomers. The decremental effect of dexamethasone was amplified by (R)-enantiomers but inhibited by (S)-enantiomers. Both propranolol and ICI-118,551 alone increased GM-CSF release in a concentration-dependent fashion, similar to (S)-enantiomers.


CONCLUSIONS
We conclude that GM-CSF release by HASMC is downregulated by (R)-enantiomers and enhanced by (S)-enantiomers. The reversal of (R)-enantiomer and dexamethasone effects by the (S)-enantiomer suggests suppression of their anti-inflammatory effects, perhaps through an antagonistic mechanism similar to propranolol.
Asthma, Allergy, and Airway Research Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, PA 15213, USA. amerdesbt@upmc.edu
Bill T
BT
Ameredes
William J
WJ
Calhoun
D000318:Adrenergic beta-Agonists / Q000737:chemistry / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D013237:Stereoisomerism
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D011412:Propanolamines; C026777:ICI 118551; D001285:Atropine; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011433:Propranolol; D000242:Cyclic AMP