Abstract
Objectiveβ2-Adrenoceptor agonists are widely used to treat asthma because of their bronchial-dilation effects. We previously reported that isoprenaline, via the apical and basolateral β2-adrenoceptor, induced Cl− secretion by activating cyclic AMP (cAMP)-dependent pathways in human bronchial epithelia. Despite these results, whether and how the β2-adrenoceptor-mediated cAMP-dependent pathway contributes to pro-inflammatory cytokine release in human bronchial epithelia remains poorly understood.MethodsWe investigated β2-adrenoceptor-mediated signaling pathways involved in the production of two pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, in 16HBE14o- human bronchial epithelia. The effects of isoprenaline or formoterol were assessed in the presence of protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), Src, and extracellular signal-regulated protein kinase (ERK)1/2 inhibitors. The involvement of β-arrestin2 was examined using siRNA knockdown.ResultsIsoprenaline and formoterol (both β2 agonists) induced IL-6, but not IL-8, release, which could be inhibited by ICI 118,551 (β2 antagonist). The PKA-specific inhibitor, H89, partially inhibited IL-6 release. Another intracellular cAMP receptor, EPAC, was not involved in IL-6 release. Isoprenaline-mediated IL-6 secretion was attenuated by dasatinib, a Src inhibitor, and PD98059, an ERK1/2 inhibitor. Isoprenaline treatment also led to ERK1/2 phosphorylation. In addition, knockdown of β-arrestin2 by siRNA specifically suppressed cytokine release when a high concentration of isoprenaline (1 mM) was used.ConclusionOur results suggest that activation of the β2-adrenoceptor in 16HBE14o- cells stimulated the PKA/Src/ERK1/2 and/or β-arrestin2 signaling pathways, leading to IL-6 release. Therefore, our data reveal that β2-adrenoceptor signaling plays a role in the immune regulation of human airway epithelia.
Highlights
Objective β2-Adrenoceptor agonists are widely used to treat asthma because of their bronchial-dilation effects
We recently reported that isoprenaline stimulated β2-adrenoceptors and induced C l− secretion, which was mediated through the cyclic AMP (cAMP)-dependent protein kinase A (PKA) pathway, leading to the activation of cystic fibrosis transmembrane conductance regulator (CFTR) in human bronchial epithelia [7]
We examined the involvement of both PKA and exchange protein directly activated by cAMP (EPAC) in β2-adrenoceptor activation to expand our knowledge of cAMP-dependent pathways in asthma
Summary
Objective β2-Adrenoceptor agonists are widely used to treat asthma because of their bronchial-dilation effects. We previously reported that isoprenaline, via the apical and basolateral β2-adrenoceptor, induced Cl− secretion by activating cyclic AMP (cAMP)-dependent pathways in human bronchial epithelia. The effects of isoprenaline or formoterol were assessed in the presence of protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), Src, and extracellular signal-regulated protein kinase (ERK)1/2 inhibitors. Conclusion Our results suggest that activation of the β2-adrenoceptor in 16HBE14o- cells stimulated the PKA/Src/ERK1/2 and/or β-arrestin signaling pathways, leading to IL-6 release. We recently reported that isoprenaline stimulated β2-adrenoceptors and induced C l− secretion, which was mediated through the cAMP-dependent protein kinase A (PKA) pathway, leading to the activation of cystic fibrosis transmembrane conductance regulator (CFTR) in human bronchial epithelia [7]. Whether the cAMP/PKA signaling pathway is involved in aggravating inflammation by promoting secretion of pro-inflammatory cytokines remains largely unknown. The latest findings indicate that β-arrestins, acting as scaffolds to recruit signaling molecules, are capable of activating Src family non-receptor tyrosine kinases and mitogenactivated protein kinases (MAPKs), which proceed to activate pro-inflammatory cytokine release [11, 12]
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