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.
Ameredes
Bill T
BT
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
Calhoun
William J
WJ
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