The flavonoid cyanidin blocks binding of the cytokine interleukin-17A to the IL-17RA subunit to alleviate inflammation in vivo

  • Sci Signal. 2017 Feb 21;10(467):eaaf8823. doi: 10.1126/scisignal.aaf8823.
Caini Liu  1 ,  Liang Zhu  2  3 ,  Koichi Fukuda  2 ,  Suidong Ouyang  1 ,  Xing Chen  1 ,  Chenhui Wang  1  4 ,  Cun-Jin Zhang  1  5 ,  Bradley Martin  1 ,  Chunfang Gu  1 ,  Luke Qin  1 ,  Suguna Rachakonda  6 ,  Mark Aronica  7 ,  Jun Qin  8  3 ,  Xiaoxia Li  9
Affiliations
  • 1. Department of Immunology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
  • 2. Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 3. Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
  • 4. 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.
  • 5. Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
  • 6. National Institutes of Health Center for Accelerated Innovations, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 7. Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 8. Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. [email protected] [email protected].
  • 9. Department of Immunology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. [email protected] [email protected].
PMID: 28223414 DOI: 10.1126/scisignal.aaf8823
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.

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