ACUTE HEPATOTOXICITY OF PSEUDOMONAS-AERUGINOSA EXOTOXIN-A IN MICE DEPENDS ON T-CELLS AND TNF

The most potent virulence factor of Pseudomonas aeruginosa, its exotos in A (PEA), inhibits protein synthesis, especially in the liver, and i s a weak T cell mitogen. This study was performed to correlate hepatot oxic and possible immunostimulatory features of PEA in vivo. Injection of PEA to mice caused hepatocyte apoptosis, an increase in plasma tra nsaminase activities, and the release of TNF, IFN-gamma, IL-2, and IL- 6 into the circulation. Most strikingly, liver damage depended on T ce lls. Athymic nude mice or mice depleted of T cells by anti-Thy1.2 mAb pretreatment failed to develop acute hepatic failure, and survival was significantly prolonged following T cell depletion. Neutralization of TNF or lack of TNF receptors prevented liver injury. In the liver, TN F was produced by Kupffer cells before hepatocellular death occurred. After T cell depletion, Kupffer cells failed to produce TNF. Transamin ase release was significantly reduced in perforin knockout mice, and i t was even elevated in lpr/lpr mice. These results demonstrate that PE A induces liver damage not only by protein synthesis inhibition but al so by TNF- and perforin-dependent, Pas-independent, apoptotic signals.