Endotoxin-inducible granulocyte-mediated hepatocytotoxicity requires adhesion and serine protease release

Achim Sauer, Thomas Hartung, Joachim Aigner, Albrecht Wendel

Research output: Contribution to journalArticlepeer-review

Abstract

In primary cultures of Kupffer cells and hepatocytes, human granulocytes potentiated toxicity of endotoxin about 1000-fold. Granulocyte elastase activity was found to correlate with toxicity. The serine protease inhibitors α1-antitrypsin, eglin C, and aprotinin protected against toxicity. Tumor necrosis factor-α (TNF-α) induced cytotoxicity and elastase release, whereas neutralization of TNF-α blocked both events. We conclude that TNF-α formed by Kupffer cells activates granulocytes, Experiments in cultures where cells were separated by membranes permeable to mediators indicated that cell contact is needed for toxicity. Scanning electron microscopy showed granulocytes adhering to and interdigitating with hepatocytes. Using liver cells from ICAM-1-deficient mice had no effect on toxicity. However, neutralizing CD31 inhibited toxicity and elastase release but not granulocyte adhesion. Our findings demonstrate that adhesion of granulocytes is a necessary but not sufficient condition for the synergistic interaction of endotoxin-stimulated liver macrophages and granulocytes in the proteolytic killing of hepatocytes.

Original languageEnglish (US)
Pages (from-to)633-643
Number of pages11
JournalJournal of Leukocyte Biology
Volume60
Issue number5
DOIs
StatePublished - Nov 1996
Externally publishedYes

Keywords

  • CD31
  • Elastase
  • Inflammation
  • Polymorphonuclear neutrophilic granulocyte
  • Septic organ failure
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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