Long-acting β2-adrenoreceptor agonists suppress type 1 interferon expression in human plasmacytoid dendritic cells via epigenetic regulation

Chang Hung Kuo; San Nan Yang; Yi Giien Tsai; Chong Chao Hsieh; Wei Ting Liao; Li Chen Chen; Min Sheng Lee; Hsuan Fu Kuo; Ching Hsiung Lin; Chih Hsing Hung

doi:10.1016/j.pupt.2017.10.004

Long-acting β2-adrenoreceptor agonists suppress type 1 interferon expression in human plasmacytoid dendritic cells via epigenetic regulation

Chang Hung Kuo
, San Nan Yang
, Yi Giien Tsai
, Chong Chao Hsieh
, Wei Ting Liao
, Li Chen Chen
, Min Sheng Lee
, Hsuan Fu Kuo
, Ching Hsiung Lin
, Chih Hsing Hung^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

10 Scopus citations

Abstract

The combination of inhaled long-acting β2-adrenoreceptor (LABA) and inhaled glucocorticoid (ICS) is a major therapy for asthma. However, the increased risk of infection is still a concern. Plasmacytoid dendritic cells (pDCs) are the predominant cells producing type 1 interferon (IFN) against infection. The effect of LABA/ICS on type 1 IFN expression in human pDCs is unknown. Circulating pDCs were isolated from healthy human subjects and were pretreated with glucocorticoid (GCS), LABA or a cAMP analog, and were stimulated with Toll-like receptor (TLR) agonist CpG (TLR9) or imiquimod (TLR7) in the presence of IL-3. The expression of type 1 IFN (IFN-α/β) were measured by ELISA. The mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting and chromatin immunoprecipitation. GCS suppressed TLR-induced IFN-α expression, and LABA enhanced the suppressive effect. LABA alone also suppressed TLR-induced IFN-α/β expression, and the effect was reversed by the β2-adrenoreceptor antagonist ICI118551. Dibutyryl-cAMP, a cAMP analog, conferred a similar suppressive effect, and the effect was abrogated by the exchange protein directly activated by cAMP (Epac) inhibitor HJC0197 or intracellular free Ca²⁺ chelator BAPTA-AM. Formoterol suppressed TLR-induced phosphorylation of mitogen-activated protein kinase (MAPK)-p38/ERK. Formoterol suppressed interferon regulatory factor (IRF)-3/IRF-7 expression. Formoterol suppressed CpG-induced translocation of H3K4 specific methyltransferase WDR5 and suppressed H3K4 trimethylation in the IFNA and IFNB gene promoter region. LABA suppressed TLR7/9-induced type 1 IFNs production, at least partly, via the β₂-adrenoreceptor-cAMP-Epac-Ca²⁺, IRF-3/IRF-7, the MAPK-p38/ERK pathway, and epigenetic regulation by suppressing histone H3K4 trimethylation through inhibiting the translocation of WDR5 from cytoplasm to nucleus. LABA may interfere with anti-viral immunity.

Original language	English
Pages (from-to)	37-45
Number of pages	9
Journal	Pulmonary Pharmacology and Therapeutics
Volume	48
DOIs	https://doi.org/10.1016/j.pupt.2017.10.004
State	Published - 02 2018
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2017

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Corticosteroid
Dendritic cell
Epigenetics
Long-acting β2-adrenoreceptor agonist
Type 1 interferon

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10.1016/j.pupt.2017.10.004

Cite this

Kuo, C. H., Yang, S. N., Tsai, Y. G., Hsieh, C. C., Liao, W. T., Chen, L. C., Lee, M. S., Kuo, H. F., Lin, C. H., & Hung, C. H. (2018). Long-acting β2-adrenoreceptor agonists suppress type 1 interferon expression in human plasmacytoid dendritic cells via epigenetic regulation. Pulmonary Pharmacology and Therapeutics, 48, 37-45. https://doi.org/10.1016/j.pupt.2017.10.004

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title = "Long-acting β2-adrenoreceptor agonists suppress type 1 interferon expression in human plasmacytoid dendritic cells via epigenetic regulation",

abstract = "The combination of inhaled long-acting β2-adrenoreceptor (LABA) and inhaled glucocorticoid (ICS) is a major therapy for asthma. However, the increased risk of infection is still a concern. Plasmacytoid dendritic cells (pDCs) are the predominant cells producing type 1 interferon (IFN) against infection. The effect of LABA/ICS on type 1 IFN expression in human pDCs is unknown. Circulating pDCs were isolated from healthy human subjects and were pretreated with glucocorticoid (GCS), LABA or a cAMP analog, and were stimulated with Toll-like receptor (TLR) agonist CpG (TLR9) or imiquimod (TLR7) in the presence of IL-3. The expression of type 1 IFN (IFN-α/β) were measured by ELISA. The mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting and chromatin immunoprecipitation. GCS suppressed TLR-induced IFN-α expression, and LABA enhanced the suppressive effect. LABA alone also suppressed TLR-induced IFN-α/β expression, and the effect was reversed by the β2-adrenoreceptor antagonist ICI118551. Dibutyryl-cAMP, a cAMP analog, conferred a similar suppressive effect, and the effect was abrogated by the exchange protein directly activated by cAMP (Epac) inhibitor HJC0197 or intracellular free Ca2+ chelator BAPTA-AM. Formoterol suppressed TLR-induced phosphorylation of mitogen-activated protein kinase (MAPK)-p38/ERK. Formoterol suppressed interferon regulatory factor (IRF)-3/IRF-7 expression. Formoterol suppressed CpG-induced translocation of H3K4 specific methyltransferase WDR5 and suppressed H3K4 trimethylation in the IFNA and IFNB gene promoter region. LABA suppressed TLR7/9-induced type 1 IFNs production, at least partly, via the β2-adrenoreceptor-cAMP-Epac-Ca2+, IRF-3/IRF-7, the MAPK-p38/ERK pathway, and epigenetic regulation by suppressing histone H3K4 trimethylation through inhibiting the translocation of WDR5 from cytoplasm to nucleus. LABA may interfere with anti-viral immunity.",

keywords = "Corticosteroid, Dendritic cell, Epigenetics, Long-acting β2-adrenoreceptor agonist, Type 1 interferon",

author = "Kuo, \{Chang Hung\} and Yang, \{San Nan\} and Tsai, \{Yi Giien\} and Hsieh, \{Chong Chao\} and Liao, \{Wei Ting\} and Chen, \{Li Chen\} and Lee, \{Min Sheng\} and Kuo, \{Hsuan Fu\} and Lin, \{Ching Hsiung\} and Hung, \{Chih Hsing\}",

note = "Publisher Copyright: {\textcopyright} 2017",

year = "2018",

month = feb,

doi = "10.1016/j.pupt.2017.10.004",

language = "英语",

volume = "48",

pages = "37--45",

journal = "Pulmonary Pharmacology and Therapeutics",

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TY - JOUR

T1 - Long-acting β2-adrenoreceptor agonists suppress type 1 interferon expression in human plasmacytoid dendritic cells via epigenetic regulation

AU - Kuo, Chang Hung

AU - Yang, San Nan

AU - Tsai, Yi Giien

AU - Hsieh, Chong Chao

AU - Liao, Wei Ting

AU - Chen, Li Chen

AU - Lee, Min Sheng

AU - Kuo, Hsuan Fu

AU - Lin, Ching Hsiung

AU - Hung, Chih Hsing

PY - 2018/2

Y1 - 2018/2

N2 - The combination of inhaled long-acting β2-adrenoreceptor (LABA) and inhaled glucocorticoid (ICS) is a major therapy for asthma. However, the increased risk of infection is still a concern. Plasmacytoid dendritic cells (pDCs) are the predominant cells producing type 1 interferon (IFN) against infection. The effect of LABA/ICS on type 1 IFN expression in human pDCs is unknown. Circulating pDCs were isolated from healthy human subjects and were pretreated with glucocorticoid (GCS), LABA or a cAMP analog, and were stimulated with Toll-like receptor (TLR) agonist CpG (TLR9) or imiquimod (TLR7) in the presence of IL-3. The expression of type 1 IFN (IFN-α/β) were measured by ELISA. The mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting and chromatin immunoprecipitation. GCS suppressed TLR-induced IFN-α expression, and LABA enhanced the suppressive effect. LABA alone also suppressed TLR-induced IFN-α/β expression, and the effect was reversed by the β2-adrenoreceptor antagonist ICI118551. Dibutyryl-cAMP, a cAMP analog, conferred a similar suppressive effect, and the effect was abrogated by the exchange protein directly activated by cAMP (Epac) inhibitor HJC0197 or intracellular free Ca2+ chelator BAPTA-AM. Formoterol suppressed TLR-induced phosphorylation of mitogen-activated protein kinase (MAPK)-p38/ERK. Formoterol suppressed interferon regulatory factor (IRF)-3/IRF-7 expression. Formoterol suppressed CpG-induced translocation of H3K4 specific methyltransferase WDR5 and suppressed H3K4 trimethylation in the IFNA and IFNB gene promoter region. LABA suppressed TLR7/9-induced type 1 IFNs production, at least partly, via the β2-adrenoreceptor-cAMP-Epac-Ca2+, IRF-3/IRF-7, the MAPK-p38/ERK pathway, and epigenetic regulation by suppressing histone H3K4 trimethylation through inhibiting the translocation of WDR5 from cytoplasm to nucleus. LABA may interfere with anti-viral immunity.

AB - The combination of inhaled long-acting β2-adrenoreceptor (LABA) and inhaled glucocorticoid (ICS) is a major therapy for asthma. However, the increased risk of infection is still a concern. Plasmacytoid dendritic cells (pDCs) are the predominant cells producing type 1 interferon (IFN) against infection. The effect of LABA/ICS on type 1 IFN expression in human pDCs is unknown. Circulating pDCs were isolated from healthy human subjects and were pretreated with glucocorticoid (GCS), LABA or a cAMP analog, and were stimulated with Toll-like receptor (TLR) agonist CpG (TLR9) or imiquimod (TLR7) in the presence of IL-3. The expression of type 1 IFN (IFN-α/β) were measured by ELISA. The mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting and chromatin immunoprecipitation. GCS suppressed TLR-induced IFN-α expression, and LABA enhanced the suppressive effect. LABA alone also suppressed TLR-induced IFN-α/β expression, and the effect was reversed by the β2-adrenoreceptor antagonist ICI118551. Dibutyryl-cAMP, a cAMP analog, conferred a similar suppressive effect, and the effect was abrogated by the exchange protein directly activated by cAMP (Epac) inhibitor HJC0197 or intracellular free Ca2+ chelator BAPTA-AM. Formoterol suppressed TLR-induced phosphorylation of mitogen-activated protein kinase (MAPK)-p38/ERK. Formoterol suppressed interferon regulatory factor (IRF)-3/IRF-7 expression. Formoterol suppressed CpG-induced translocation of H3K4 specific methyltransferase WDR5 and suppressed H3K4 trimethylation in the IFNA and IFNB gene promoter region. LABA suppressed TLR7/9-induced type 1 IFNs production, at least partly, via the β2-adrenoreceptor-cAMP-Epac-Ca2+, IRF-3/IRF-7, the MAPK-p38/ERK pathway, and epigenetic regulation by suppressing histone H3K4 trimethylation through inhibiting the translocation of WDR5 from cytoplasm to nucleus. LABA may interfere with anti-viral immunity.

KW - Corticosteroid

KW - Dendritic cell

KW - Epigenetics

KW - Long-acting β2-adrenoreceptor agonist

KW - Type 1 interferon

UR - https://www.scopus.com/pages/publications/85032830179

U2 - 10.1016/j.pupt.2017.10.004

DO - 10.1016/j.pupt.2017.10.004

M3 - 文章

C2 - 28987803

AN - SCOPUS:85032830179

SN - 1094-5539

VL - 48

SP - 37

EP - 45

JO - Pulmonary Pharmacology and Therapeutics

JF - Pulmonary Pharmacology and Therapeutics

ER -

Long-acting β2-adrenoreceptor agonists suppress type 1 interferon expression in human plasmacytoid dendritic cells via epigenetic regulation

Abstract

Bibliographical note

UN SDGs

Keywords

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