title: Formoterol synergy with des-ciclesonide inhibits IL-4 expression in IgE/antigen-induced mast cells by inhibiting JNK activation.
abstract: Inhaled corticosteroid (ICS) therapy in combination with long-acting β-adrenergic agonists (LABA) is the most important treatment for allergic asthma, although the mechanism still remains unclear. However, mast cells play a central role in the pathogenesis of asthma. In this study, we explored the sole or synergetic effects of des-ciclesonide (ICS) and formoterol (LABA) on the cytokines IL-4 and IL-13 and on histamine release from mast cells (RBL-2H3 cells). We found that des-ciclesonide (0.1, 1 and 10nM) and formoterol (0.1, 1 and 10μM) alone attenuated DNP-BSA-induced IL-4 and IL-13 production, respectively, in a concentration-dependent manner in DNP-IgE-sensitized mast cells. Des-ciclesonide (0.2nM) and formoterol (1μM) alone also reduced histamine production. However, the combination of des-ciclesonide (0.2nM) and formoterol (1μM) had a synergistic inhibition effect on IL-4 mRNA expression and protein production but not IL-13 and histamine release. The JNK inhibitor SP600125 (10μM) inhibited antigen-induced mRNA expression and protein production of IL-4. Des-ciclesonide and formoterol alone inhibited the activation of JNK in a concentration-dependent manner, and the combination of des-ciclesonide (0.2nM) and formoterol (1μM) exhibited greater inhibition effect compared with des-ciclesonide (0.2nM) or formoterol (1μM) alone. Taken together, these synergistic effects on mast cells might provide the rationale for the development of the most recent ICS/LABA combination approved for asthma therapy.
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of CFDA, Medical College of Zhejiang University, Hangzhou 310058, China.
authors.forename: Yan-hong
authors.initials: YH
authors.lastname: Sun
authors.affiliation: Medical College, Yangzhou University, 11 Huaihai Road, Yangzhou City, Jiangsu Province 225001, China.
authors.forename: Ling-tian
authors.initials: LT
authors.lastname: Ge
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of CFDA, Medical College of Zhejiang University, Hangzhou 310058, China.
authors.forename: Jun-xia
authors.initials: JX
authors.lastname: Jiang
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of CFDA, Medical College of Zhejiang University, Hangzhou 310058, China.
authors.forename: Hui-juan
authors.initials: HJ
authors.lastname: Shen
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of CFDA, Medical College of Zhejiang University, Hangzhou 310058, China.
authors.forename: Yong-liang
authors.initials: YL
authors.lastname: Jia
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of CFDA, Medical College of Zhejiang University, Hangzhou 310058, China.
authors.forename: Xin-wei
authors.initials: XW
authors.lastname: Dong
authors.affiliation: Medical College, Yangzhou University, 11 Huaihai Road, Yangzhou City, Jiangsu Province 225001, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of CFDA, Medical College of Zhejiang University, Hangzhou 310058, China. Electronic address: xieqm@zju.edu.cn.
authors.forename: Qiang-min
authors.initials: QM
authors.lastname: Xie
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D004140:Dinitrophenols / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004789:Enzyme Activation; D000068759:Formoterol Fumarate / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006636:Histamine Release / Q000187:drug effects; D007073:Immunoglobulin E / Q000276:immunology*; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D010766:Phosphorylation; D011282:Pregnenediones / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012710:Serum Albumin, Bovine / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D004140:Dinitrophenols; D018793:Interleukin-13; D011282:Pregnenediones; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C034638:dinitrophenyl-bovine serum albumin; D015847:Interleukin-4; D012710:Serum Albumin, Bovine; D007073:Immunoglobulin E; C494355:desisobutyrylciclesonide; D048031:JNK Mitogen-Activated Protein Kinases; D000068759:Formoterol Fumarate
keywords: Ciclesonide; Combination; Formoterol; IL-4; Mast cells