Berberine improved experimental chronic colitis by regulating interferon-\u03b3- and IL-17A-producing lamina propria CD4+ T cells through AMPK activation

Masahiro Takahara,Toshihiro Inokuchi,Heiichiro Udono,Sakiko Hiraoka,Keita Harada,Takuya Adachi,Hiroshi Matsushita,Tien Thi Thuy Nguyen,Kazuko Koike,Shiho Takashima,Hiroyuki Okada,Yusaku Sugihara,Airi Ikeda,Akinobu Takaki,Yasushi Yamasaki,Shingo Eikawa,Yasuyuki Shimomura,Hideaki Kinugasa,Hidetoshi Morita

doi:10.1038/s41598-019-48331-w

Masahiro Takahara, Toshihiro Inokuchi + Show 17 more

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https://doi.org/10.1038/s41598-019-48331-w

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Journal: Scientific Reports	Publication Date: Aug 15, 2019
Citations: 59	License type: open-access

Affiliation: Okayama University, Hue University

Abstract

The herbal medicine berberine (BBR) has been recently shown to be an AMP-activated protein kinase (AMPK) productive activator with various properties that induce anti-inflammatory responses. We investigated the effects of BBR on the mechanisms of mucosal CD4+T cell activation in vitro and on the inflammatory responses in T cell transfer mouse models of inflammatory bowel disease (IBD). We examined the favorable effects of BBR in vitro, using lamina propria (LP) CD4+ T cells in T cell transfer IBD models in which SCID mice had been injected with CD4+CD45RBhigh T cells. BBR suppressed the frequency of IFN-γ- and Il-17A-producing LP CD4+ T cells. This effect was found to be regulated by AMPK activation possibly induced by oxidative phosphorylation inhibition. We then examined the effects of BBR on the same IBD models in vivo. BBR-fed mice showed AMPK activation in the LPCD4+ T cells and an improvement of colitis. Our study newly showed that the BBR-induced AMPK activation of mucosal CD4+ T cells resulted in an improvement of IBD and underscored the importance of AMPK activity in colonic inflammation.

Highlights

(AMPK) productive activator with various properties that induce anti-inflammatory responses
We investigated the effect and inhibitory mechanisms of BBR on lamina propria (LP) CD4+ T cells of Inflammatory bowel disease (IBD)—in terms of the cellular energy metabolism related to AMPK activity—using a T cell transfer colitis model involving the transfer of naïve (CD4+CD45RBhigh) T cells into congenic immunodeficiency mice to induce CD4+ T cell-specific colitis
LP CD4+ T cells of colitis SCID mice injected with CD4+ CD45RBhigh T cells were isolated and stimulated with PMA plus ionomycin mixed with BBR or not

Summary

Introduction

(AMPK) productive activator with various properties that induce anti-inflammatory responses. We investigated the effects of BBR on the mechanisms of mucosal CD4+T cell activation in vitro and on the inflammatory responses in T cell transfer mouse models of inflammatory bowel disease (IBD). BBR suppressed the frequency of IFN-γ- and Il-17A-producing LP CD4+ T cells This effect was found to be regulated by AMPK activation possibly induced by oxidative phosphorylation inhibition. Our study newly showed that the BBR-induced AMPK activation of mucosal CD4+ T cells resulted in an improvement of IBD and underscored the importance of AMPK activity in colonic inflammation. Accumulating evidence suggests that IBD is caused by an inappropriate response of the innate and acquired immune systems to the commensal microbiota[1] Among these immune systems, inflammatory CD4+ T cells in the colonic lamina propria (LP) are acknowledged as critical factors in the pathogenesis of IBD2. AMPK signaling has been shown to www.nature.com/scientificreports/

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