Effects of minocycline on Fas-mediated fulminant hepatitis in mice

Heng-Cheng Chu, Yi-Ling Lin, Huey-Kang Sytwu, Shin-Hua Lin, Ching-Len Liao, You-Chen Chao

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21 Citations (Scopus)

Abstract

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. Intraperitoneal injection of Jo2 (0.6 μg 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. 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. 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.
Original languageEnglish
Pages (from-to)275-282
Number of pages8
JournalBritish Journal of Pharmacology
Volume144
Issue number2
DOIs
Publication statusPublished - 2005
Externally publishedYes

Keywords

  • Caspase
  • Cytochrome c
  • Fas
  • Fulminant hepatitis
  • Minocycline
  • Mitochondria
  • caspase 3
  • caspase 9
  • cytochrome c
  • Fas antibody
  • Fas antigen
  • jo2 antibody
  • liver extract
  • minocycline
  • protein Bid
  • unclassified drug
  • alanine aminotransferase blood level
  • animal experiment
  • animal model
  • animal tissue
  • antiinflammatory activity
  • apoptosis
  • article
  • aspartate aminotransferase blood level
  • controlled study
  • disease model
  • drug effect
  • enzyme activation
  • enzyme release
  • hepatitis
  • histopathology
  • kinetics
  • liver mitochondrion
  • male
  • mouse
  • mouse strain
  • nonhuman
  • priority journal
  • survival
  • Animals
  • Antibodies, Monoclonal
  • Antigens, CD95
  • Dose-Response Relationship, Drug
  • Liver
  • Liver Failure, Acute
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Tumor Necrosis Factor

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  • Cite this

    Chu, H-C., Lin, Y-L., Sytwu, H-K., Lin, S-H., Liao, C-L., & Chao, Y-C. (2005). Effects of minocycline on Fas-mediated fulminant hepatitis in mice. British Journal of Pharmacology, 144(2), 275-282. https://doi.org/10.1038/sj.bjp.0706079