1. ¹Graduate Institute of Medical Sciences, Taipei, Taiwan, Republic of China
2. ²Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan, Republic of China
3. ³Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
4. ⁴Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China

Correspondence: C-L Liao, 161, Sec. 6, Min-Chuan E Road, Neihu, Taipei 114, Taiwan, Republic of China. E-mail: chinglen@ms1.hinet.net; Y-C Chao, 325, Sec. 2, Cheng-Kung Road, Neihu, Taipei 114, Taiwan, Republic of China. E-mail: gi@ndmctsgh.edu.tw

Received 1 June 2004; Accepted 30 June 2004; Published online 13 December 2004.

Abstract

1. Minocycline has anti-inflammatory and antiapoptotic effects on cartilage, neurons and periodontal tissues, and both properties are central to the pharmaceutical treatment of liver diseases. We investigated the effects of minocycline on fulminant hepatitis in C57BL/6J mice induced by lethal challenge of the activating anti-Fas antibody, Jo2.
2. Intraperitoneal injection of Jo2 (0.6 g g^-1) to mice resulted in fulminant hepatitis, as evidenced by increase of serum alanine/aspartate transaminase activities and histopathological alterations in liver sections, as well as animal death. Nevertheless, mice pretreated with three doses of minocycline (5 mg kg^-1) resisted this lethal effect significantly. Minocycline treatment improved the survival kinetics, although to a lesser extent, when mice were challenged simultaneously with Jo2 or even treated 30 min after the lethal challenge.
3. Jo2-induced activation of caspase-3 or -9 in liver tissues was inhibited by minocycline pretreatment, and yet the direct addition of minocycline to liver extracts from Jo2-challenged mice failed to block caspase activation in vitro. Moreover, minocycline efficiently suppressed the release of cytochrome c from mitochondria of the liver tissues from Jo2-challenged mice. In contrast, caspase-8 activation and Bid truncation triggered by Jo2 were not diminished by minocycline pretreatment in mouse livers.
4. Our results suggest that easing of Fas-triggered fulminant hepatitis by minocycline may involve a mitochondrial apoptotic pathway, probably through preventing cytochrome c release and thereby blocking downstream caspase activation.