title: The flavonoid cyanidin blocks binding of the cytokine interleukin-17A to the IL-17RA subunit to alleviate inflammation in vivo.
abstract: Cyanidin, a key flavonoid that is present in red berries and other fruits, attenuates the development of several diseases, including asthma, diabetes, atherosclerosis, and cancer, through its anti-inflammatory effects. We investigated the molecular basis of cyanidin action. Through a structure-based search for small molecules that inhibit signaling by the proinflammatory cytokine interleukin-17A (IL-17A), we found that cyanidin specifically recognizes an IL-17A binding site in the IL-17A receptor subunit (IL-17RA) and inhibits the IL-17A/IL-17RA interaction. Experiments with mice demonstrated that cyanidin inhibited IL-17A-induced skin hyperplasia, attenuated inflammation induced by IL-17-producing T helper 17 (TH17) cells (but not that induced by TH1 or TH2 cells), and alleviated airway hyperreactivity in models of steroid-resistant and severe asthma. Our findings uncover a previously uncharacterized molecular mechanism of action of cyanidin, which may inform its further development into an effective small-molecule drug for the treatment of IL-17A-dependent inflammatory diseases and cancer.
authors.affiliation: Department of Immunology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Caini
authors.identifier: 0000-0002-9314-7145
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.|Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Liang
authors.identifier: 0000-0002-6529-5706
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Department of Immunology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Suidong
authors.identifier: 0000-0001-5002-6995
authors.initials: S
authors.lastname: Ouyang
authors.affiliation: Department of Immunology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Xing
authors.identifier: 0000-0001-9727-3598
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Immunology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.|Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
authors.forename: Chenhui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Immunology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.|Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Cun-Jin
authors.initials: CJ
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Martin
authors.affiliation: Department of Immunology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Chunfang
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of Immunology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Luke
authors.identifier: 0000-0003-1575-4289
authors.initials: L
authors.lastname: Qin
authors.affiliation: National Institutes of Health Center for Accelerated Innovations, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Suguna
authors.initials: S
authors.lastname: Rachakonda
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Aronica
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. qinj@ccf.org lix@ccf.org.|Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Immunology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. qinj@ccf.org lix@ccf.org.
authors.forename: Xiaoxia
authors.identifier: 0000-0002-4872-9525
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D000872:Anthocyanins / Q000737:chemistry / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D053722:Receptors, Interleukin-17 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D000872:Anthocyanins; D000893:Anti-Inflammatory Agents; C508717:IL17A protein, human; C109985:IL17RA protein, human; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; C017154:cyanidin