期刊
BIOCHEMICAL PHARMACOLOGY
卷 77, 期 11, 页码 1717-1724出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2009.03.002
关键词
Apoptosis; Activated T cells; Selective; Fraxinellone; Concanavalin A
资金
- National Natural Science Foundation of China [30730107]
- Natural Science Foundation of Jiangsu Province [BK2007716, BK2008271]
Selectively inducing apoptosis of activated T cells is essential for the clearance of pathogenic injurious cells and subsequent efficient resolution of inflammation. However, few chemicals have been reported to trigger apoptosis of activated T cells in the treatment of hepatitis without affecting quiescent T cells. In the present study, we found that fraxinellone, a small natural compound isolated from the root bark of Dictamnus dasycarpus, selectively facilitated apoptosis of concanavalin A (Con A)-activated CD4(+) T cells rather than those non-activated, by disrupting the mitochondrial transmembrane potential, decreasing the ratio of Bcl-2/Bax, and increasing cytochrome c release from the mitochondria to the cytosol. The enhancement in Fas expression and caspase-8 activity, truncation of Bid, and down-regulation of antiapoptotic cellular FLICE-inhibitory protein expression by fraxinellone also suggested the participation of an extrinsic apoptosis pathway. Furthermore, fraxinellone significantly alleviated Con A-induced T-cell-dependent hepatitis in mice, which was closely associated with reduced serum transaminases, pro-inflammatory cytokines, and pathologic parameters. Consistent with the in vitro results, fraxinellone dramatically induced apoptosis of activated peripheral CD4(+)T cells in vivo, consequently resulting in less CD4(+) T-cell activation and infiltration to the liver. These results strongly suggest fraxinellone might be a potential leading compound useful in treating T-cell-mediated liver disorders in humans. (c) 2009 Elsevier Inc. All rights reserved.
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