Mitochondria-Dependent Apoptosis of Con A-Activated T Lymphocytes Induced by Asiatic Acid for Preventing Murine Fulminant Hepatitis

Wenjie Guo,Wen Liu,Qiang Xu,Shaocheng Hong,Yan Shen,Xuefeng Wu,Yang Sun,Hailiang Liu,Cheng Qian,Andrew D Badley

doi:10.1371/journal.pone.0046018

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 MRLlpr/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.

Highlights

Immune responses are frequently characterized by major expansions of antigen-specific T cells that have potent effector functions
In order to examine the effect of asiatic acid on T cells, lymph node-derived T cells isolated from BALB/c mice were incubated in medium or in the presence of concanavalin A (Con A) or anti-CD3/anti-CD28 or PMA/ionomycin for 24 h
Specific induction of pathogenic T cell apoptosis is beneficial in depressing excess immune responses and maintaining immune homeostasis, and represents a new approach for future treatment of numerous T-cell-mediated immune diseases

Summary

Introduction

Immune responses are frequently characterized by major expansions of antigen-specific T cells that have potent effector functions. Eliminate the unwanted activated T cells through facilitating apoptosis may provide a strategy for the treatment of T celldependent diseases Such a strategy focusing on the pathogenic T cells may avoid intervention of normal immune responses to other foreign without affecting naive or non-activated T cells. Three different death signaling pathways lead to apoptosis such as the extrinsic death receptor pathway, the intrinsic mitochondrion-dependent pathway and the intrinsic endoplasmic reticulum (ER) stress pathway [5]. These pathways work together to regulate the function of T cells [6]. Stimulation of death receptors such as Fas or TNF-related apoptosis-inducing ligand receptors results in receptor aggregation and recruitment of the adaptor molecule Fas-associated death domain and caspase-8 [8]

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