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

Caini Liu; Liang Zhu; Koichi Fukuda; Suidong Ouyang; Xing Chen; Chenhui Wang; Cun-Jin Zhang; Bradley Martin; Chunfang Gu; Luke Qin; Suguna Rachakonda; Mark Aronica; Jun Qin; Xiaoxia Li

doi:10.1126/scisignal.aaf8823

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.

Authors

Caini Liu¹, Liang Zhu^{2

3}, Koichi Fukuda², Suidong Ouyang¹, Xing Chen¹, Chenhui Wang^{1

4}, Cun-Jin Zhang^{1

5}, Bradley Martin¹, Chunfang Gu¹, Luke Qin¹, Suguna Rachakonda⁶, Mark Aronica⁷, Jun Qin^{8

3}, Xiaoxia Li⁹

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].

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 (T_H17) cells (but not that induced by T_H1 or T_H2 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anthocyanins* / chemistry
Anthocyanins* / pharmacology
Anti-Inflammatory Agents* / chemistry
Anti-Inflammatory Agents* / pharmacology
Binding Sites
Humans
Inflammation / immunology
Inflammation / pathology
Interleukin-17* / antagonists & inhibitors
Interleukin-17* / chemistry
Interleukin-17* / immunology
Mice
Mice, Transgenic
Receptors, Interleukin-17* / antagonists & inhibitors
Receptors, Interleukin-17* / chemistry
Receptors, Interleukin-17* / immunology
Th17 Cells / immunology
Th17 Cells / pathology

Substances

Anthocyanins
Anti-Inflammatory Agents
IL17A protein, human
IL17RA protein, human
Interleukin-17
Receptors, Interleukin-17
cyanidin

Abstract

Publication types

MeSH terms

Substances

Grants and funding