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β(2)-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia
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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626360/ https://www.ncbi.nlm.nih.gov/pubmed/34725715 http://dx.doi.org/10.1007/s00408-021-00484-0 |
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author | Zhang, Rui-Gang Niu, Ya Pan, Ke-Wu Pang, Hao Chen, Chun-Ling Yip, Chung-Yin Ko, Wing-Hung |
author_facet | Zhang, Rui-Gang Niu, Ya Pan, Ke-Wu Pang, Hao Chen, Chun-Ling Yip, Chung-Yin Ko, Wing-Hung |
author_sort | Zhang, Rui-Gang |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8626360 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-86263602021-12-01 β(2)-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia Zhang, Rui-Gang Niu, Ya Pan, Ke-Wu Pang, Hao Chen, Chun-Ling Yip, Chung-Yin Ko, Wing-Hung Lung Beta-2-Adrenoceptors in Human Bronchial Epithelia 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. Springer US 2021-11-01 2021 /pmc/articles/PMC8626360/ /pubmed/34725715 http://dx.doi.org/10.1007/s00408-021-00484-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Beta-2-Adrenoceptors in Human Bronchial Epithelia Zhang, Rui-Gang Niu, Ya Pan, Ke-Wu Pang, Hao Chen, Chun-Ling Yip, Chung-Yin Ko, Wing-Hung β(2)-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia |
title | β(2)-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia |
title_full | β(2)-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia |
title_fullStr | β(2)-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia |
title_full_unstemmed | β(2)-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia |
title_short | β(2)-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia |
title_sort | β(2)-adrenoceptor activation stimulates il-6 production via pka, erk1/2, src, and beta-arrestin2 signaling pathways in human bronchial epithelia |
topic | Beta-2-Adrenoceptors in Human Bronchial Epithelia |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626360/ https://www.ncbi.nlm.nih.gov/pubmed/34725715 http://dx.doi.org/10.1007/s00408-021-00484-0 |
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