ENDOTOXIN-INDUCIBLE GRANULOCYTE-MEDIATED HEPATOCYTOTOXICITY REQUIRES ADHESION AND SERINE-PROTEASE RELEASE

In primary cultures of Kupffer cells and hepatocytes, human granulocyt es potentiated toxicity of endotoxin about 1000-fold, Granulocyte elas tase activity was found to correlate with toxicity, The serine proteas e inhibitors al-antitrypsin, eglin C, and aprotinin protected against toxicity, Tumor necrosis factor-alpha (TNF-alpha) induced cytotoxicity and elastase release, whereas neutralization of TNF-alpha blocked bot h events, We conclude that TNF-alpha formed by Kupffer cells activates granulocytes, Experiments in cultures where cells were separated by m embranes permeable to mediators indicated that cell contact is needed for toxicity, Scanning electron microscopy showed granulocytes adherin g to and interdigitating with hepatocytes. Using liver cells from ICAM -1-deficient mice had no effect on toxicity, However, neutralizing CD3 1 inhibited toxicity and elastase release but not granulocyte adhesion , Our findings demonstrate that adhesion of granulocytes is a necessar y but not sufficient condition for the synergistic interaction of endo toxin-stimulated liver macrophages and granulocytes in the proteolytic killing of hepatocytes.