title: TLR2 activation causes tachyphylaxis to β2 -agonists in vitro and ex vivo: modelling bacterial exacerbation.
abstract: BACKGROUND
  Asthma is a widespread chronic health problem exacerbated by common viral and bacterial infections. Further research is required to understand how infection worsens asthma control in order to advance therapeutic options in the future. Recent research has revealed that β2 -adrenergic receptor (β2 -AR) agonists lose bronchodilatory efficacy because the receptor-mediated molecular pathways responsible for their beneficial actions are desensitized by infection. To date, most studies have focussed on viral infection, leaving the impact of bacterial infection on β2 -AR desensitization relatively under-investigated. We address this in this study.
  
  
  RESULTS
  Utilizing an in vitro model of bacterial exacerbation in airway smooth muscle (ASM) cells, we show that activation of toll-like receptor 2 (TLR2; mimicking bacterial infection) in the presence of an inflammatory stimulus leads to β2 -AR desensitization. This occurs via TLR2-dependent upregulation of cyclooxygenase 2 (COX-2) mRNA expression and increased secretion of PGE2 . Importantly, PGE2 causes heterologous β2 -AR desensitization and reduces cAMP production in response to short-acting (salbutamol) and long-acting (formoterol) β2 -agonists. Thus, bacterial infectious stimuli act in a PGE2 -dependent manner to severely curtail the beneficial actions of β2 -agonists. The impact of β2 -AR desensitization is demonstrated by reduced gene expression of the critical anti-inflammatory molecule MKP-1 in response to β2 -agonists, as well as impaired bronchodilation in a mouse lung slices.
  
  
  CONCLUSIONS
  Taken together, our results show that, like viruses, bacteria induce prostanoid-dependent β2 -AR desensitization on ASM cells. Notably, COX-2 inhibition with the specific inhibitor celecoxib represses PGE2 secretion, presenting a feasible pharmacological option for treatment of infectious exacerbation in asthma in the future.
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Alkhouri
authors.forename: N N
authors.initials: NN
authors.lastname: Rumzhum
authors.forename: M M
authors.initials: MM
authors.lastname: Rahman
authors.forename: M
authors.initials: M
authors.lastname: FitzPatrick
authors.forename: M
authors.initials: M
authors.lastname: de Pedro
authors.forename: B G
authors.initials: BG
authors.lastname: Oliver
authors.forename: J E
authors.initials: JE
authors.lastname: Bourke
authors.forename: A J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D001424:Bacterial Infections / Q000150:complications* / Q000276:immunology / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000276:immunology; D015232:Dinoprostone / Q000096:biosynthesis / Q000276:immunology; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013618:Tachyphylaxis / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018927:Anti-Asthmatic Agents; D018343:Receptors, Adrenergic, beta-2; D051195:Toll-Like Receptor 2; D051546:Cyclooxygenase 2; D054638:Dual Specificity Phosphatase 1; D015232:Dinoprostone
keywords: adrenergic agonists; bacteria; beta-2 adrenergic receptors; tachyphylaxis; toll-like receptor 2