Research ArticleInflammation

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

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Sci. Signal.  21 Feb 2017:
Vol. 10, Issue 467, eaaf8823
DOI: 10.1126/scisignal.aaf8823

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How red berries reduce inflammation

Members of the interleukin-17 (IL-17) family of proinflammatory cytokines are important in the immune response to infections; however, excessive IL-17 signaling is associated with autoimmune inflammatory diseases, such as asthma, psoriasis, and rheumatoid arthritis. Through a screen of small molecules, Liu et al. found that cyanidin, a flavonoid found in red berries and other fruits, bound to the IL-17 receptor (IL-17RA) in a manner that blocked the binding of IL-17A. In several mouse models of inflammatory disease, cyanidin alleviated inflammation induced by T cells that produce IL-17A. Together, these data suggest that cyanidin should be further developed as a small-molecule inhibitor of IL-17A–dependent inflammatory diseases.

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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