Effects of minocycline on Fas-mediated fulminant hepatitis in mice.
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 microg 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.
Chu
Heng-Cheng
HC
Graduate Institute of Medical Sciences, Taipei, Taiwan, Republic of China.
Lin
Yi-Ling
YL
Sytwu
Huey-Kang
HK
Lin
Shin-Hua
SH
Liao
Ching-Len
CL
Chao
You-Chen
YC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000633:toxicity; D058846:Antibodies, Monoclonal, Murine-Derived; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019014:fas Receptor
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; C491899:Fas protein, mouse; D018124:Receptors, Tumor Necrosis Factor; C411023:anti-Fas monoclonal antibody; D019014:fas Receptor; D008911:Minocycline