Journal Article

Protection against Fas Receptor–Mediated Apoptosis in Hepatocytes and Nonparenchymal Cells by a Caspase-8 Inhibitor <i>in Vivo</i>: Evidence for a Postmitochondrial Processing of Caspase-8

Mary Lynn Bajt, Judy A. Lawson, Steven L. Vonderfecht, Jaspreet S. Gujral and Hartmut Jaeschke

in Toxicological Sciences

Volume 58, issue 1, pages 109-117
Published in print November 2000 | ISSN: 1096-6080
Published online November 2000 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/58.1.109
Protection against Fas Receptor–Mediated Apoptosis in Hepatocytes and Nonparenchymal Cells by a Caspase-8 Inhibitor in Vivo: Evidence for a Postmitochondrial Processing of Caspase-8

More Like This

Show all results sharing these subjects:

  • Medical Toxicology
  • Toxicology (Non-medical)

GO

Show Summary Details

Preview

Lymphocytes can kill target cells including hepatocytes during various inflammatory diseases by Fas receptor–mediated apoptosis. Caspase-8 is activated at the receptor level, thereby initiating the processing of downstream effector caspases. The aim of this study was to investigate the time course of caspase-8 activation and to evaluate the efficacy of the caspase-8 inhibitor IETD-CHO in a model of Fas-induced apoptosis in vivo. C3Heb/FeJ mice were treated with the anti-Fas antibody Jo-2 (0.6 mg/kg). Western blot analysis demonstrated increased cytochrome c in the cytosol (20 min), which was followed by the progressive activation of caspase-3, -9 (40–120 min), and caspase-8 (120 min). At 90 and 120 min, extensive hemorrhage was observed, indicating damage to sinusoidal lining cells. In addition, high plasma ALT levels (997 ± 316 U/L) and histological evaluation indicated severe parenchymal cell injury. Parenchymal and nonparenchymal cells showed a similar increase in caspase-3 activity and DNA fragmentation. Treatment with IETD-CHO (10 mg/kg) attenuated the increase in caspase-3 activity and DNA fragmentation by 80–90% and completely prevented hemorrhage and parenchymal cell damage. IETD-CHO also prevented the early release of mitochondrial cytochrome c and the processing of caspase-3, -8, and -9. Thus, our data support the hypothesis that Fas-mediated apoptosis is dependent on caspase-8 activation in hepatocytes and nonparenchymal cells. However, the bulk of procaspase-8 is processed late, suggesting that only a small amount of procaspase-8 may actually be activated at the Fas receptor. This initial signal may be amplified by further activation of caspase-8 by effector caspases, i.e., after mitochondrial activation. Caspase-8 is a promising therapeutic target for inhibition of Fas-mediated apoptosis.

Keywords: liver cell apoptosis; Fas-induced liver failure; caspase cascade; mitochondria; cytochrome c; IETD-CHO; caspase-8 inhibitor

Journal Article.  6402 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.