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

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)65-72
Number of pages8
JournalJournal of Allergy and Clinical Immunology
Volume116
Issue number1
DOIs
StatePublished - Jul 2005
Externally publishedYes

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Granulocyte-Macrophage Colony-Stimulating Factor
Smooth Muscle
Propranolol
Dexamethasone
Smooth Muscle Myocytes
Anti-Inflammatory Agents
Adrenergic Agonists
Albuterol
Conditioned Culture Medium
Interleukin-1
Down-Regulation
Enzyme-Linked Immunosorbent Assay
Pharmaceutical Preparations

Keywords

  • β-receptors
  • Albuterol
  • cAMP
  • Formoterol
  • Inverse agonist
  • Levalbuterol
  • Propranolol
  • Racemic

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

@article{1207648f0a1c479582e04b3c8ec2b851,
title = "Modulation of GM-CSF release by enantiomers of β-agonists in human airway smooth muscle",
abstract = "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.",
keywords = "β-receptors, Albuterol, cAMP, Formoterol, Inverse agonist, Levalbuterol, Propranolol, Racemic",
author = "Bill Ameredes and William Calhoun",
year = "2005",
month = "7",
doi = "10.1016/j.jaci.2005.03.007",
language = "English (US)",
volume = "116",
pages = "65--72",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "1",

}

TY - JOUR

T1 - Modulation of GM-CSF release by enantiomers of β-agonists in human airway smooth muscle

AU - Ameredes, Bill

AU - Calhoun, William

PY - 2005/7

Y1 - 2005/7

N2 - 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.

AB - 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.

KW - β-receptors

KW - Albuterol

KW - cAMP

KW - Formoterol

KW - Inverse agonist

KW - Levalbuterol

KW - Propranolol

KW - Racemic

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