Premium
TLR2 activation causes tachyphylaxis to β 2 ‐agonists in vitro and ex vivo: modelling bacterial exacerbation
Author(s) -
Alkhouri H.,
Rumzhum N. N.,
Rahman M. M.,
FitzPatrick M.,
Pedro M.,
Oliver B. G.,
Bourke J. E.,
Ammit A. J.
Publication year - 2014
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.12449
Subject(s) - tachyphylaxis , desensitization (medicine) , tlr2 , agonist , formoterol , receptor , ex vivo , immunology , downregulation and upregulation , in vivo , medicine , inflammation , tlr4 , biology , pharmacology , asthma , biochemistry , microbiology and biotechnology , budesonide , gene
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 β 2 ‐adrenergic receptor (β 2 ‐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 β 2 ‐ AR desensitization relatively under‐investigated. We address this in this study. Methods and 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 β 2 ‐AR desensitization. This occurs via TLR2‐dependent upregulation of cyclooxygenase 2 (COX‐2) mRNA expression and increased secretion of PGE 2 . Importantly, PGE 2 causes heterologous β 2 ‐AR desensitization and reduces cAMP production in response to short‐acting (salbutamol) and long‐acting (formoterol) β 2 ‐agonists. Thus, bacterial infectious stimuli act in a PGE 2 ‐dependent manner to severely curtail the beneficial actions of β 2 ‐agonists. The impact of β 2 ‐AR desensitization is demonstrated by reduced gene expression of the critical anti‐inflammatory molecule MKP‐1 in response to β 2 ‐agonists, as well as impaired bronchodilation in a mouse lung slices. Conclusions Taken together, our results show that, like viruses, bacteria induce prostanoid‐dependent β 2 ‐ AR desensitization on ASM cells. Notably, COX ‐2 inhibition with the specific inhibitor celecoxib represses PGE 2 secretion, presenting a feasible pharmacological option for treatment of infectious exacerbation in asthma in the future.