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*
Institute of Experimental and Clinical Pharmacology and Toxicology, and
Institute of Clinical Microbiology and Immunology, University of Erlangen-Nurnberg, Erlangen, Germany; and
Department of Anatomy and Cell Biology II, University of Heidelberg, Heidelberg, Germany
The most potent virulence factor of Pseudomonas
aeruginosa, its exotoxin A (PEA), inhibits protein synthesis,
especially in the liver, and is a weak T cell mitogen. This study was
performed to correlate hepatotoxic and possible immunostimulatory
features of PEA in vivo. Injection of PEA to mice caused hepatocyte
apoptosis, an increase in plasma transaminase activities, and the
release of TNF, IFN-
, IL-2, and IL-6 into the circulation. Most
strikingly, liver damage depended on T cells. 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, TNF was produced by
Kupffer cells before hepatocellular death occurred. After T cell
depletion, Kupffer cells failed to produce TNF. Transaminase release
was significantly reduced in perforin knockout mice, and it was even
elevated in lpr/lpr mice. These results demonstrate that
PEA induces liver damage not only by protein synthesis inhibition but
also by TNF- and perforin-dependent, Fas-independent, apoptotic
signals.
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