Cysteinyl leukotriene receptor antagonist epigenetically modulates cytokine expression and maturation of human myeloid dendritic cells

Chang-Hung Kuo; San-Nan Yang; Hsuan-Fu Kuo; Min-Sheng Lee; Ming-Yii Huang; Shau-Ku Huang; Yi-Ching Lin; Chong-Chao Hsieh; Chih-Hsing Hung

doi:10.1016/j.pupt.2016.06.001

Cysteinyl leukotriene receptor antagonist epigenetically modulates cytokine expression and maturation of human myeloid dendritic cells

Pulm Pharmacol Ther. 2016 Aug:39:28-37. doi: 10.1016/j.pupt.2016.06.001. Epub 2016 Jun 14.

Authors

Chang-Hung Kuo¹, San-Nan Yang², Hsuan-Fu Kuo³, Min-Sheng Lee⁴, Ming-Yii Huang⁵, Shau-Ku Huang⁶, Yi-Ching Lin⁷, Chong-Chao Hsieh⁸, Chih-Hsing Hung⁹

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 Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
⁴ Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
⁵ Department of Radiation Oncology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
⁶ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Johns Hopkins University School of Medicine, Baltimore, MD, USA; National Health Research Institutes, Miaoli County, Taiwan.
⁷ Department of Laboratory Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁸ Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
⁹ Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pediatrics, School 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: 27312202
DOI: 10.1016/j.pupt.2016.06.001

Abstract

Background: Cysteinyl leukotriene receptor antagonists are important controllers in treating asthma. Human myeloid DCs (mDCs) play critical roles in the pathogenesis of asthma. However, the effects of cysteinyl leukotriene receptor antagonist on human mDCs are unknown.

Methods: To investigate the effects of cysteinyl leukotriene receptor antagonist on the function of human mDCs, circulating mDCs were isolated from six health subjects. Human mDCs were pretreated with montelukast and were stimulated with toll-like receptor (TLR) ligands lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly I:C). Tumor necrosis factor (TNF)-α and interleukin (IL)-10 were measured by ELISA. Intracellular signaling was investigated by pathway inhibitors, western blot and chromatin immunoprecipitation. Costimulatory molecules expression was investigated by flow cytometry. T cell polarization function of mDCs was investigated by measuring interferon (IFN)-γ, IL-13, IL-10 and IL-17A production by T cells using mDC/T cell coculture assay.

Results: Montelukast suppressed TLR-mediated TNF-α expression via the NFκB-p65 and mitogen-activated protein kinase (MAPK)-JNK pathway, and enhanced TLR-mediated IL-10 expression via the MAPK-p38 pathway and epigenetic regulation by histone H3 acetylation. Montelukast suppressed LPS-induced CD80, CD86, CD40 and HLA-DR expression. Montelukast-treated mDCs suppressed IFN-γ and IL-13 production by T cells.

Conclusion: Cysteinyl leukotriene receptor antagonist alters the function of human mDCs by epigenetically modulating cytokine expression, suppressing costimulatory molecules expression and inhibiting the ability to initiate Th1/Th2 responses. The effects of cysteinyl leukotriene receptor antagonist on human mDCs can be an important mechanism in treating asthma.

Keywords: Cysteinyl leukotriene receptor antagonist; Dendritic cell; Epigenetics; Interleukin-10; Tumor necrosis factor-α.

MeSH terms

Acetates / pharmacology*
Anti-Asthmatic Agents / pharmacology
Cyclopropanes
Cytokines / metabolism
Dendritic Cells / drug effects*
Dendritic Cells / metabolism
Enzyme-Linked Immunosorbent Assay
Epigenesis, Genetic
Humans
Interleukin-10 / metabolism
Leukotriene Antagonists / pharmacology*
Lipopolysaccharides / pharmacology
Poly I-C / pharmacology
Quinolines / pharmacology*
Receptors, Leukotriene / drug effects*
Receptors, Leukotriene / metabolism
Sulfides
Th1 Cells / metabolism
Th2 Cells / metabolism
Tumor Necrosis Factor-alpha / metabolism

Substances

Acetates
Anti-Asthmatic Agents
Cyclopropanes
Cytokines
Leukotriene Antagonists
Lipopolysaccharides
Quinolines
Receptors, Leukotriene
Sulfides
Tumor Necrosis Factor-alpha
Interleukin-10
leukotriene D4 receptor
montelukast
Poly I-C