β 2 -Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia.

Autor: Zhang RG; Department of Physiology, Basic Medical School, Guangdong Medical University, Zhanjiang, China., Niu Y; Department of Physiology, Basic Medical School, Guangdong Medical University, Zhanjiang, China., Pan KW; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, N.T., China., Pang H; Department of Physiology, Basic Medical School, Guangdong Medical University, Zhanjiang, China., Chen CL; Department of Physiology, Basic Medical School, Guangdong Medical University, Zhanjiang, China., Yip CY; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, N.T., China., Ko WH; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, N.T., China. whko@cuhk.edu.hk.
Jazyk: angličtina
Zdroj: Lung [Lung] 2021 Dec; Vol. 199 (6), pp. 619-627. Date of Electronic Publication: 2021 Nov 01.
DOI: 10.1007/s00408-021-00484-0
Abstrakt: Objective: β 2 -Adrenoceptor agonists are widely used to treat asthma because of their bronchial-dilation effects. We previously reported that isoprenaline, via the apical and basolateral β 2 -adrenoceptor, induced Cl - secretion by activating cyclic AMP (cAMP)-dependent pathways in human bronchial epithelia. Despite these results, whether and how the β 2 -adrenoceptor-mediated cAMP-dependent pathway contributes to pro-inflammatory cytokine release in human bronchial epithelia remains poorly understood.
Methods: We investigated β 2 -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.
Results: Isoprenaline and formoterol (both β 2 agonists) induced IL-6, but not IL-8, release, which could be inhibited by ICI 118,551 (β 2 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.
Conclusion: Our results suggest that activation of the β 2 -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 β 2 -adrenoceptor signaling plays a role in the immune regulation of human airway epithelia.
(© 2021. The Author(s).)
Databáze: MEDLINE
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