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

Pulm Pharmacol Ther. 2018 Feb:48:37-45. doi: 10.1016/j.pupt.2017.10.004. Epub 2017 Oct 5.

Authors

Affiliations

¹ Ta-Kuo Clinic, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan.
² School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; Department of Pediatrics, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan.
³ Department of Pediatrics, Changhua Christian Children's Hospital, Changhua, Taiwan; School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
⁴ Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
⁵ Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁶ The Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
⁷ Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁸ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
⁹ School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Division of Chest Medicine, Changhua Christian Hospital, Changhua, Taiwan.
¹⁰ School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; Research Center of Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: pedhung@gmail.com.

PMID: 28987803
DOI: 10.1016/j.pupt.2017.10.004

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adrenergic beta-2 Receptor Agonists / administration & dosage
Adrenergic beta-2 Receptor Agonists / pharmacology*
Blotting, Western
Chromatin Immunoprecipitation
Cyclic AMP / metabolism
Dendritic Cells / drug effects*
Drug Therapy, Combination
Enzyme-Linked Immunosorbent Assay
Epigenesis, Genetic
Formoterol Fumarate / administration & dosage
Formoterol Fumarate / pharmacology*
Glucocorticoids / administration & dosage
Glucocorticoids / pharmacology*
Humans
Imiquimod / pharmacology
Interferon-alpha / genetics
Interferon-alpha / metabolism
Interferon-beta / genetics
Interferon-beta / metabolism
Propanolamines / pharmacology
Toll-Like Receptor 7 / metabolism
Toll-Like Receptor 9 / metabolism

Substances

Adrenergic beta-2 Receptor Agonists
Glucocorticoids
Interferon-alpha
Propanolamines
TLR7 protein, human
TLR9 protein, human
Toll-Like Receptor 7
Toll-Like Receptor 9
ICI 118551
Interferon-beta
Cyclic AMP
Imiquimod
Formoterol Fumarate