Modulation of GM-CSF release by enantiomers of β-agonists in human airway smooth muscle

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.

Key words: Albuterol, β-receptors, cAMP, formoterol, inverse agonist, levalbuterol, propranolol, racemic

Abbreviations used: cAMP, Cyclic adenosine monophosphate, HASMC, Human airway smooth muscle cell