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The contribution of gene expression changes to the adverse and therapeutic effects of β  2 -adrenoceptor agonists in asthma was investigated using human airway epithelial cells as a therapeutically relevant target. Operational model-fitting established that the long-acting β  2 -adrenoceptor agonists (LABA) indacaterol, salmeterol, formoterol, and picumeterol were full agonists on BEAS-2B cells transfected with a cAMP-response element reporter but differed in efficacy (indacaterol ≥ formoterol &gt; salmeterol ≥ picumeterol). The transcriptomic signature of indacaterol in BEAS-2B cells identified 180, 368, 252, and 10 genes that were differentially expressed (&gt;1.5- to &lt;0.67-fold) after 1-, 2-, 6-, and 18-hour of exposure, respectively. Many upregulated genes (e.g., AREG , BDNF , CCL20 , CXCL2 , EDN1 , IL6 , IL15 , IL20 ) encode proteins with proinflammatory activity and are annotated by several, enriched gene ontology (GO) terms, including cellular response to interleukin-1 , cytokine activity , and positive regulation of neutrophil chemotaxis The general enriched GO term extracellular space was also associated with indacaterol-induced genes, and many of those, including CRISPLD2 , DMBT1 , GAS1, and SOCS3, have putative anti-inflammatory, antibacterial, and/or antiviral activity. Numerous indacaterol-regulated genes were also induced or repressed in BEAS-2B cells and human primary bronchial epithelial cells by the low efficacy LABA salmeterol, indicating that this genomic effect was neither unique to indacaterol nor restricted to the BEAS-2B airway epithelial cell line. Collectively, these data suggest that the consequences of inhaling a β  2 -adrenoceptor agonist may be complex and involve widespread changes in gene expression. We propose that this genomic effect represents a generally unappreciated mechanism that may contribute to the adverse and therapeutic actions of β  2 -adrenoceptor agonists in asthma.

the journal of pharmacology and experimental therapeutics/the journal of pharmacology and experimental therapeutics

Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the Adverse and Therapeutic Effects of<i>β</i><sub>2</sub>-Adrenoceptor Agonists

Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the Adverse and Therapeutic Effects ofβ2-Adrenoceptor Agonists

Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the Adverse and Therapeutic Effects ofβ₂-Adrenoceptor Agonists