title: The Flavonoid 7,4'-Dihydroxyflavone Prevents Dexamethasone Paradoxical Adverse Effect on Eotaxin Production by Human Fibroblasts.
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.
authors.affiliation: Department of Pediatric Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Changda
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pediatric Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Pediatric Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.|Respiratory Department, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA.
authors.forename: Jody
authors.initials: J
authors.lastname: Tversky
authors.affiliation: Department of Biological Engineering, Utah State University, 4105 Old Main Hill, Logan, UT, 84322, USA.
authors.forename: Jixun
authors.initials: J
authors.lastname: Zhan
authors.affiliation: Department of Pediatric Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Mirna
authors.initials: M
authors.lastname: Chehade
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University, New York, NY, 10032, USA.|Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University, New York, NY, 10032, USA.|Department of Environmental Health Sciences, Columbia University, New York, NY, 10032, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Miller
authors.affiliation: Department of Pediatric Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
authors.forename: Xiu-Min
authors.initials: XM
authors.lastname: Li
mesh_terms: D001249:Asthma / Q000378:metabolism; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000378:metabolism*; D003907:Dexamethasone / Q000009:adverse effects*; D004347:Drug Interactions; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D047309:Flavones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D005938:Glucocorticoids / Q000009:adverse effects; D029882:Glycyrrhiza uralensis / Q000737:chemistry; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C000618353:7,4'-dihydroxyflavone; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D047309:Flavones; D005419:Flavonoids; D005938:Glucocorticoids; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D003907:Dexamethasone; D056464:Histone Deacetylase 2
keywords: Glycyrrhiza uralensis; STAT6; corticosteroids; lung fibroblasts