Enhancement of inflammatory mediator release by beta(2)-adrenoceptor agonists in airway epithelial cells is reversed by glucocorticoid action

Br J Pharmacol. 2010 May;160(2):410-20. doi: 10.1111/j.1476-5381.2010.00708.x.


Background and purpose: Due to their potent bronchodilator properties, beta(2)-adrenoceptor agonists are a mainstay of therapy in asthma. However, the effects of beta(2)-adrenoceptor agonists on inflammation are less clear. Accordingly, we have investigated the effects of beta(2)-adrenoceptor agonists on inflammatory mediator release.

Experimental approach: Transcription factor activation, and both release and mRNA expression of IL-6 and IL-8 were examined by luciferase reporter assay, elisa and real-time RT-PCR in bronchial human epithelial BEAS-2B cells or primary human bronchial epithelial cells grown at an air-liquid interface.

Key results: Pre-incubation with beta(2)-adrenoceptor agonists (salbutamol, salmeterol, formoterol) augmented the release and mRNA expression of IL-6 and IL-8 induced by IL-1beta and IL-1beta plus histamine, whereas NF-kappaB-dependent transcription was significantly repressed, and AP-1-dependent transcription was unaffected. These effects were mimicked by other cAMP-elevating agents (PGE(2), forskolin). Enhancement of cytokine release by beta(2)-adrenoceptor agonists also occurred in primary bronchial epithelial cells. Addition of dexamethasone with salmeterol repressed IL-6 and IL-8 release to levels that were similar to the repression achieved in the absence of salmeterol. IL-6 release was enhanced when salmeterol was added before, concurrently or after IL-1beta plus histamine stimulation, whereas IL-8 release was only enhanced by salmeterol addition prior to stimulation.

Conclusions and implications: Enhancement of IL-6 and IL-8 release may contribute to the deleterious effects of beta(2)-adrenoceptor agonists in asthma. As increased inflammatory mediator expression is prevented by the addition of glucocorticoid to the beta(2)-adrenoceptor, our data provide further mechanistic support for the use of combination therapies in asthma management.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists*
  • Adrenergic beta-Agonists / pharmacology*
  • Adrenergic beta-Agonists / toxicity
  • Albuterol / analogs & derivatives
  • Albuterol / pharmacology
  • Albuterol / toxicity
  • Asthma / drug therapy
  • Asthma / physiopathology
  • Bronchi / cytology
  • Bronchi / drug effects
  • Bronchodilator Agents / pharmacology*
  • Bronchodilator Agents / toxicity
  • Cell Line
  • Dexamethasone / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Ethanolamines / pharmacology
  • Ethanolamines / toxicity
  • Formoterol Fumarate
  • Gene Expression Regulation / drug effects
  • Glucocorticoids / pharmacology*
  • Humans
  • Inflammation Mediators / metabolism
  • Interleukin-6 / genetics
  • Interleukin-8 / genetics
  • Salmeterol Xinafoate
  • Transcription, Genetic / drug effects


  • Adrenergic beta-2 Receptor Agonists
  • Adrenergic beta-Agonists
  • Bronchodilator Agents
  • Ethanolamines
  • Glucocorticoids
  • Inflammation Mediators
  • Interleukin-6
  • Interleukin-8
  • Salmeterol Xinafoate
  • Dexamethasone
  • Albuterol
  • Formoterol Fumarate