title: Enhancement of inflammatory mediator release by beta(2)-adrenoceptor agonists in airway epithelial cells is reversed by glucocorticoid action.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Cell Biology and Anatomy, University of Calgary, Alberta, Canada. nholden@ucalgary.ca <nholden@ucalgary.ca>
authors.forename: N S
authors.initials: NS
authors.lastname: Holden
authors.forename: C F
authors.initials: CF
authors.lastname: Rider
authors.forename: M J
authors.initials: MJ
authors.lastname: Bell
authors.forename: J
authors.initials: J
authors.lastname: Velayudhan
authors.forename: E M
authors.initials: EM
authors.lastname: King
authors.forename: M
authors.initials: M
authors.lastname: Kaur
authors.forename: M
authors.initials: M
authors.lastname: Salmon
authors.forename: M A
authors.initials: MA
authors.lastname: Giembycz
authors.forename: R
authors.initials: R
authors.lastname: Newton
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology* / Q000633:toxicity; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D001980:Bronchi / Q000166:cytology / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology / Q000633:toxicity; D000068759:Formoterol Fumarate; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D000068299:Salmeterol Xinafoate; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D004983:Ethanolamines; D005938:Glucocorticoids; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D000068299:Salmeterol Xinafoate; D003907:Dexamethasone; D000420:Albuterol; D000068759:Formoterol Fumarate