Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.

Abstract

Arctigenin, the main effective constituent of Arctium lappa L. fruit, has previously been proven to dramatically attenuate dextran sulfate sodium (DSS)-induced colitis in mice, a frequently used animal model of inflammatory bowel disease (IBD). As Th1 and Th17 cells play a crucial role in the pathogenesis of IBD, the present study addressed whether and how arctigenin exerted anti-colitis efficacy by interfering with the differentiation and activation of Th1/Th17 cells. In vitro, arctigenin was shown to markedly inhibit the differentiation of Th17 cells from naïve T cells, and moderately inhibit the differentiation of Th1 cells, which was accompanied by lowered phosphorylation of STAT3 and STAT4, respectively. In contrast, arctigenin was lack of marked effect on the differentiation of either Th2 or regulatory T cells. Furthermore, arctigenin was shown to suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway in T cells as demonstrated by down-regulated phosphorylation of the downstream target genes p70S6K and RPS6, and it functioned independent of two well-known upstream kinases PI3K/AKT and ERK. Arctigenin was also able to inhibit the activity of mTORC1 by dissociating raptor from mTOR. Interestingly, the inhibitory effect of arctigenin on T cell differentiation disappeared under a status of mTORC1 overactivation via knockdown of tuberous sclerosis complex 2 (TSC2, a negative regulator of mTORC1) or pretreatment of leucine (an agonist of mTOR). In DSS-induced mice, the inhibition of Th1/Th17 responses and anti-colitis effect of arctigenin were abrogated by leucine treatment. In conclusion, arctigenin ameliorates colitis through down-regulating the differentiation of Th1 and Th17 cells via mTORC1 pathway.

• Authors: Xin Wu, Yannong Dou, Yan Yang, Difei Bian, Jinque Luo, Bei Tong, Yufeng Xia, Yue Dai
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 96 Issue 4 Pg. 323-36 (Aug 15 2015) ISSN: 1873-2968 [Electronic] England
• PMID: 26074264 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Furans
• Lignans
• Multiprotein Complexes
• Dextran Sulfate
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• arctigenin

Topics

• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Cell Differentiation (drug effects)
• Colitis (chemically induced, drug therapy, pathology)
• Dextran Sulfate
• Furans (therapeutic use)
• Humans
• Jurkat Cells
• Lignans (therapeutic use)
• Male
• Mechanistic Target of Rapamycin Complex 1
• Mice, Inbred C57BL
• Multiprotein Complexes (metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Th1 Cells (drug effects, pathology)
• Th17 Cells (drug effects, pathology)