The Flavonoid 7,4′‐Dihydroxyflavone Prevents Dexamethasone Paradoxical Adverse Effect on Eotaxin Production by Human Fibroblasts |
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| Authors: | Changda Liu Nan Yang Xiaoke Chen Jody Tversky Jixun Zhan Mirna Chehade Rachel L. Miller Xiu‐Min Li |
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| Affiliation: | 1. Department of Pediatric Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA;2. Respiratory Department, The Eighth Affiliated Hospital, Sun Yat‐sen University, Shenzhen, China;3. Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA;4. Department of Biological Engineering, Utah State University, Logan, UT, USA;5. Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University, New York, NY, USA;6. Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University, New York, NY, USA;7. Department of Environmental Health Sciences, Columbia University, New York, NY, USA |
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| Abstract: | Eotaxin/CCL‐11 is a major chemoattractant that contributes to eosinophilic inflammation in asthma. Glucocorticoids inhibit inflammation, but long‐time exposure may cause paradoxical adverse effects by augmenting eotaxin/CCL‐11production. The aim of this study was to determine if 7,4′‐dihydroxyflavone (7,4′‐DHF), the eotaxin/CCL11 inhibitor isolated from Glycyrrhiza uralensis, reduces in vitro eotaxin production induced by long‐time dexamethasone (Dex) exposure, and if so, to elucidate the mechanisms of this inhibition. Human lung fibroblast‐1 cells were used to identify the potency of 7,4′‐DHF compared with other compounds from G. uralensis, to compare 7,4′‐DHF with Dex on eotaxin production following 24‐h short‐time culture and 72‐h longer‐time (LT) culture, and to determine the effects of the 7,4′‐DHF on Dex LT culture augmented eotaxin production and molecule mechanisms. 7,4′‐DHF was the most potent eotaxin/CCL‐11 inhibitor among the ten compounds and provided continued suppression. In contrast to short‐time culture, Dex LT culture increased constitutively, and IL‐4/TNF‐α stimulated eotaxin/CCL11 production by human lung fibroblast‐1 cells. This adverse effect was abrogated by 7,4′‐DHF co‐culture. 7,4′‐DHF significantly inhibited Dex LT culture augmentation of p‐STAT6 and impaired HDAC2 expression. This study demonstrated that 7,4′‐DHF has the ability to consistently suppress eotaxin production and prevent Dex‐paradoxical adverse effects on eotaxin production. Copyright © 2017 John Wiley & Sons, Ltd. |
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| Keywords: | lung fibroblasts corticosteroids Glycyrrhiza uralensis STAT6 |
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