Mitochondria-dependent apoptosis of con A-activated T lymphocytes induced by asiatic acid for preventing murine fulminant hepatitis.

PLoS One. 2012;7(9):e46018.

Guo W, Liu W, Hong S, Liu H, Qian C, Shen Y, Wu X, Sun Y, Xu Q.

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, China.

Abstract

Selectively facilitating 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 for the treatment of hepatitis without affecting quiescent T cells. In the present study, we found that asiatic acid, a natural triterpenoid, selectively triggered apoptosis of concanavalin A (Con A)-activated T cells in a mitochondria-dependent manner indicated by the disruption of the mitochondrial transmembrane potential, release of cytochrome c from mitochondria to cytosol, caspases activation, and cleavage of PARP. In addition, asiatic acid also induced the cleavage of caspase 8 and Bid and augmented Fas expression in Con A-activated T cells. However, following activation of T cells from MRL(lpr/lpr) mice with mutation of Fas demonstrated a similar susceptibility to asiatic acid-induced apoptosis compared with normal T cells, suggesting that Fas-mediated death-receptor apoptotic pathway does not mainly contribute to asiatic acid-induced cell death. Furthermore, asiatic acid significantly alleviated Con A-induced T cell-dependent fulminant hepatitis in mice, as assessed by reduced serum transaminases, pro-inflammatory cytokines, and pathologic parameters. Consistent with the in vitro results, asiatic acid also induced apoptosis of activated CD4(+) T cells in vivo. Taken together, our results demonstrated that the ability of asiatic acid to induce apoptosis of activated T cells and its potential use in the treatment of T-cell-mediated inflammatory diseases.

PMID: 23029367

 

Supplement:

Overview of cell death pathways for asiatic acid-induced apoptosis in Con A-activated T cells. Asiatic acid triggered apoptosis of Con A-activated T cells in a mitochondria-dependent manner indicated by the disruption of the mitochondrial transmembrane potential, release of cytochrome c from mitochondria to cytosol, caspase-9 and caspase-3 activation and cleavage of PARP. At the same time, following activation of T cells from MRLlpr/lpr mice with mutation of Fas demonstrated a similar susceptibility to asiatic acid-induced apoptosis compared with normal T cells. In addition, asiatic acid hardly influenced caspase-12 activation and the expression of GRP78 and CHOP. Taken together, these results suggest that Fas-mediated death-receptor apoptotic pathway and endoplasmic reticulum (ER) stress-mediated apoptotic pathway do not mainly contribute to asiatic acid-induced cell death.

Yang Sun-1

Correspondence to

Qiang Xu, PhD, or Yang Sun, PhD, School of Life Sciences, Nanjing University, Nanjing 210093 China, Tel/Fax: +86-25-83597620; E-mail: molpharm@163.com (Q. Xu); yangsun@nju.edu.cn (Y. Sun)

Acknowledgement

This work was supported by Science Fund for Creative Research Groups of NSFC (No. 81121062), National Natural Science Foundation of China (Nos. 30973920, 81173070 and 90913023), National Science & Technology Major Project (No. 2012ZX09304-001) and National Fundamental Fund of Personnel Training in Biology (No. J1103512).

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