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The Journal of Immunology, 2005, 175: 1540-1550.
Copyright © 2005 by The American Association of Immunologists

{alpha}-Galactosylceramide-Induced Liver Injury in Mice Is Mediated by TNF-{alpha} but Independent of Kupffer Cells1

Markus Biburger and Gisa Tiegs2

Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany

NKT cells expressing phenotypic markers of both T and NK cells seem to be pivotal in murine models of immune-mediated liver injury, e.g., in Con A-induced hepatitis. Also {alpha}-galactosylceramide ({alpha}-GalCer), a specific ligand for invariant V{alpha}14 NKT cells, induces hepatic injury. To improve the comprehension of NKT-cell mediated liver injury, we investigated concomitants and prerequisites of {alpha}-GalCer-induced hepatitis in mice. Liver injury induced by {alpha}-GalCer injection into C57BL/6 mice was accompanied by intrahepatic caspase-3 activity but appeared independent thereof. {alpha}-GalCer injection also induces pronounced cytokine responses, including TNF-{alpha}, IFN-{gamma}, IL-2, IL-4, and IL-6. We provide a detailed time course for the expression of these cytokines, both in liver and plasma. Cytokine neutralization revealed that, unlike Con A-induced hepatitis, IFN-{gamma} is not only dispensable for {alpha}-GalCer-induced hepatotoxicity but even appears to exert protective effects. In contrast, TNF-{alpha} was clearly identified as an important mediator for hepatic injury in this model that increased Fas ligand expression on NKT cells. Whereas intrahepatic Kupffer cells are known as a pivotal source for TNF-{alpha} in Con A-induced hepatitis, they were nonessential for {alpha}-GalCer-mediated hepatotoxicity. In {alpha}-GalCer-treated mice, TNF-{alpha} was produced by intrahepatic lymphocytes, in particular NKT cells. BALB/c mice were significantly less susceptible to {alpha}-GalCer-induced liver injury than C57BL/6 mice, in particular upon pretreatment with D-galactosamine, a hepatocyte-specific sensitizer to TNF-{alpha}-mediated injury. Finally, we demonstrate resemblance of murine {alpha}-GalCer-induced hepatitis to human autoimmune-like liver disorders. The particular features of this model compared with other immune-mediated hepatitis models may enhance comprehension of basic mechanisms in the etiopathogenesis of NKT cell-comprising liver disorders.




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