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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.
AuthorsYan-hong Sun, Ling-tian Ge, Jun-xia Jiang, Hui-juan Shen, Yong-liang Jia, Xin-wei Dong, Yun Sun, Qiang-min Xie
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 761 Pg. 161-7 (Aug 15 2015) ISSN: 1879-0712 [Electronic] Netherlands
PMID26003274 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier B.V. All rights reserved.
Chemical References
  • Adrenal Cortex Hormones
  • Adrenergic beta-2 Receptor Agonists
  • Dinitrophenols
  • Interleukin-13
  • Pregnenediones
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • dinitrophenyl-bovine serum albumin
  • Interleukin-4
  • Serum Albumin, Bovine
  • Immunoglobulin E
  • desisobutyrylciclesonide
  • JNK Mitogen-Activated Protein Kinases
  • Formoterol Fumarate
Topics
  • Adrenal Cortex Hormones (pharmacology)
  • Adrenergic beta-2 Receptor Agonists (pharmacology)
  • Animals
  • Cell Line, Tumor
  • Dinitrophenols (immunology)
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Drug Therapy, Combination
  • Enzyme Activation
  • Formoterol Fumarate (pharmacology)
  • Gene Expression Regulation
  • Histamine Release (drug effects)
  • Immunoglobulin E (immunology)
  • Interleukin-13 (metabolism)
  • Interleukin-4 (genetics, metabolism)
  • JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
  • Mast Cells (drug effects, enzymology, immunology)
  • Phosphorylation
  • Pregnenediones (pharmacology)
  • Protein Kinase Inhibitors (pharmacology)
  • RNA, Messenger (metabolism)
  • Rats
  • Serum Albumin, Bovine (immunology)
  • Signal Transduction (drug effects)

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