Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma

Walker, Julia K. L.; DeFea, Kathryn

doi:10.1016/j.coph.2014.03.007

Cited by 39 publications

(38 citation statements)

References 55 publications

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“…Cumulative reports indicate that PAR2 activation is associated with the pathogenesis of allergic airway inflammation . PAR2‐deficient mice could not be induced airway allergy .…”

Section: Discussionmentioning

confidence: 99%

Protease‐activated receptor‐2 suppresses interleukin (IL)‐10 expression in B cells via upregulating Bcl2L12 in patients with allergic rhinitis

Xue

Yang

et al. 2017

Allergy

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“…Cumulative reports indicate that PAR2 activation is associated with the pathogenesis of allergic airway inflammation . PAR2‐deficient mice could not be induced airway allergy .…”

Section: Discussionmentioning

confidence: 99%

Protease‐activated receptor‐2 suppresses interleukin (IL)‐10 expression in B cells via upregulating Bcl2L12 in patients with allergic rhinitis

Xue

Yang

et al. 2017

Allergy

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“…β2AR activation enhances adenylate cyclase activity and cAMP synthesis, which promote smooth muscle relaxation in airways and blood vessels, enhance ciliary beating, enhancing mucin clearance. 35,36 However, repeated β2AR stimulation leads to receptor desensitization through phosphorylation of GRK2, which promotes phosphorylation and internalization of the β2AR. 12,37 This receptor activation/desensitization is complex with different mechanisms involved in different settings, although phosphorylation of β2AR is central to all.…”

Section: Discussionmentioning

confidence: 99%

IL-13 desensitizes β2-adrenergic receptors in human airway epithelial cells through a 15-lipoxygenase/G protein receptor kinase 2 mechanism

Albano

Zhao

Etling

et al. 2015

Journal of Allergy and Clinical Immunology

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Background Beta-2 adrenergic receptor (β2AR) agonists are critical treatments for asthma. However, receptor desensitization can lead to loss of therapeutic effects. While desensitization to repeated use of β2 agonists is well studied, Type-2 inflammation could also impact β2AR function. Objective To evaluate the impact of the Type-2 cytokine, IL-13, on β2AR desensitization in human airway epithelial cells (HAECs) and determine whether 15-Lipoxygenase-1 (15LO1) binding with phosphatidylethanolamine binding protein-1 (PEBP1) contributes to desensitization through release of G-protein Receptor Kinase-2 (GRK2). Methods HAECs in air-liquid-interface (ALI) culture with/without IL-13 (48 hrs) or isoproterenol (ISO) (30 min) pretreatment were stimulated with ISO (10min). cAMP was measured by ELISA and β2AR and GRK2 phosphorylation by Western Blot. siRNA was utilized for 15LO1 knockdown. Interactions of GRK2, PEBP1 and 15LO1 were detected by Immunoprecipitation/Western Blot and immunofluorescence. HAECs and airway tissue from controls and asthmatics were evaluated for I5LO1, PEBP1 and GRK2. Results Pretreatment with ISO or IL-13 decreased ISO-induced cAMP generation compared to ISO for 10 min alone, paralleled by increases in β2AR and GRK2 phosphorylation. GRK2 associated with PEBP1 after 10 min of ISO in association with low pGRK2 levels. In contrast, in the presence of IL-13+ISO (10 min), binding of GRK2 to PEBP1 decreased, while 15LO1 binding and pGRK2 increased. 15LO1 knockdown restored ISO-induced cAMP generation. These findings were recapitulated in freshly brushed HAEC from asthmatic cells and tissue. Conclusion IL-13 treatment of HAECs leads to β2AR desensitization which involves 15LO1/PEBP1 interactions to free GRK2 and allow it to phosphorylate (and desensitize) β2ARs, suggesting beneficial effects of β2 agonists could be blunted in Type-2 associated asthma.

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“…40). In vivo studies have reported that barrestin-2 null mice have shown an attenuated asthma phenotype, and we have recently shown that administration of b 2 AR ligands capable of activating ERK1/2 in vitro (10, 12) restore the asthma-like phenotype in PNMT-KO mice, and do not attenuate the asthma-like phenotype in WT mice (16).…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β₂-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

Forkuo

Kim

Thanawala

et al. 2016

Am J Respir Cell Mol Biol

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Mice lacking the endogenous b 2 -adrenoceptor (b 2 AR) agonist epinephrine (phenylethanolamine N-methyltransferase [PNMT]-knockout mice) are resistant to developing an "asthma-like" phenotype in an ovalbumin sensitization and challenge (Ova S/C) model, and chronic administration of b 2 AR agonists to PNMT-KO mice restores the phenotype. Based on these and other studies showing differential effects of various b 2 AR ligands on the asthma phenotype, we have speculated that the permissive effect of endogenous epinephrine and exogenous b 2 AR agonists on allergic lung inflammation can be explained by qualitative b 2 AR signaling. The b 2 AR can signal through at least two pathways: the canonical Gas-cAMP pathway and a b-arrestin-dependent pathway. Previous studies suggest that b-arrestin-2 is required for allergic lung inflammation. On the other hand, cell-based assays suggest antiinflammatory effects of Gas-cAMP signaling. This study was designed to test whether the in vitro antiinflammatory effects of phosphodiesterase 4 inhibitors, known to increase intracellular cAMP in multiple airway cell types, attenuate the asthma-like phenotype produced by the b 2 AR agonists formoterol and salmeterol in vivo in PNMT-KO mice, based on the hypothesis that skewing b 2 AR signaling toward Gas-cAMP pathway is beneficial. Airway inflammatory cells, epithelial mucus production, and airway hyperresponsiveness were quantified. In Ova S/C PNMT-KO mice, formoterol and salmeterol restored the asthma-like phenotype comparable to Ova S/C wild-type mice. However, coadministration of either roflumilast or rolipram attenuated this formoterol-or salmeterol-driven phenotype in Ova S/C PNMT-KO. These findings suggest that amplification of b 2 AR-mediated cAMP by phosphodiesterase 4 inhibitors attenuates the asthma-like phenotype promoted by b-agonists.

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Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma

Cited by 39 publications

References 55 publications

Protease‐activated receptor‐2 suppresses interleukin (IL)‐10 expression in B cells via upregulating Bcl2L12 in patients with allergic rhinitis

Protease‐activated receptor‐2 suppresses interleukin (IL)‐10 expression in B cells via upregulating Bcl2L12 in patients with allergic rhinitis

IL-13 desensitizes β2-adrenergic receptors in human airway epithelial cells through a 15-lipoxygenase/G protein receptor kinase 2 mechanism

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β₂-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

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Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma

Cited by 39 publications

References 55 publications

Protease‐activated receptor‐2 suppresses interleukin (IL)‐10 expression in B cells via upregulating Bcl2L12 in patients with allergic rhinitis

Protease‐activated receptor‐2 suppresses interleukin (IL)‐10 expression in B cells via upregulating Bcl2L12 in patients with allergic rhinitis

IL-13 desensitizes β2-adrenergic receptors in human airway epithelial cells through a 15-lipoxygenase/G protein receptor kinase 2 mechanism

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

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Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β₂-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice