Modulation of GM-CSF release by enantiomers of β-agonists in human airway smooth muscle
Received 15 June 2004; received in revised form 1 March 2005; accepted 7 March 2005. published online 26 April 2005.
Background
β2-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-1β, TNF-α, and IFN-γ 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.
Conclusion
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.
From the Asthma, Allergy, and Airway Research Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center
Reprint requests: Bill T. Ameredes, PhD, Research Assistant Professor of Medicine, Asthma, Allergy, and Airway Research Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, 628NW Montefiore University Hospital, 3459 Fifth Ave, Pittsburgh, PA 15213.
Supported by the American Respiratory Alliance of Western Pennsylvania and Sepracor, Inc.
Disclosure of potential conflict of interest: Bill Ameredes and William Calhoun have consultant arrangements with Sepracor, Inc, receive grant/research support from Sepracor, Inc, and are on the speakers' bureau for Sepracor, Inc.
ABSTRACT