Back to Search
Start Over
Selective triggering of apoptosis of concanavalin A-activated T cells by fraxinellone for the treatment of T-cell-dependent hepatitis in mice.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2009 Jun 01; Vol. 77 (11), pp. 1717-24. Date of Electronic Publication: 2009 Mar 14. - Publication Year :
- 2009
-
Abstract
- 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 anti-apoptotic 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.
- Subjects :
- Animals
Female
Hepatitis, Animal chemically induced
Membrane Potentials drug effects
Membrane Potentials physiology
Mice
Mice, Inbred C57BL
Mitochondrial Membranes drug effects
Mitochondrial Membranes physiology
T-Lymphocytes cytology
T-Lymphocytes drug effects
Apoptosis drug effects
Benzofurans therapeutic use
Concanavalin A pharmacology
Hepatitis, Animal drug therapy
Hepatitis, Animal immunology
Lymphocyte Activation drug effects
T-Lymphocytes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2968
- Volume :
- 77
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 19428326
- Full Text :
- https://doi.org/10.1016/j.bcp.2009.03.002