{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T08:04:42Z","timestamp":1790409882115,"version":"4.1.0"},"reference-count":65,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2005,8,1]],"date-time":"2005-08-01T00:00:00Z","timestamp":1122854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2005,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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 \u03b1-galactosylceramide (\u03b1-GalCer), a specific ligand for invariant V\u03b114 NKT cells, induces hepatic injury. To improve the comprehension of NKT-cell mediated liver injury, we investigated concomitants and prerequisites of \u03b1-GalCer-induced hepatitis in mice. Liver injury induced by \u03b1-GalCer injection into C57BL\/6 mice was accompanied by intrahepatic caspase-3 activity but appeared independent thereof. \u03b1-GalCer injection also induces pronounced cytokine responses, including TNF-\u03b1, IFN-\u03b3, 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-\u03b3 is not only dispensable for \u03b1-GalCer-induced hepatotoxicity but even appears to exert protective effects. In contrast, TNF-\u03b1 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-\u03b1 in Con A-induced hepatitis, they were nonessential for \u03b1-GalCer-mediated hepatotoxicity. In \u03b1-GalCer-treated mice, TNF-\u03b1 was produced by intrahepatic lymphocytes, in particular NKT cells. BALB\/c mice were significantly less susceptible to \u03b1-GalCer-induced liver injury than C57BL\/6 mice, in particular upon pretreatment with d-galactosamine, a hepatocyte-specific sensitizer to TNF-\u03b1-mediated injury. Finally, we demonstrate resemblance of murine \u03b1-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.<\/jats:p>","DOI":"10.4049\/jimmunol.175.3.1540","type":"journal-article","created":{"date-parts":[[2014,4,20]],"date-time":"2014-04-20T23:20:32Z","timestamp":1398036032000},"page":"1540-1550","source":"Crossref","is-referenced-by-count":143,"title":["\u03b1-Galactosylceramide-Induced Liver Injury in Mice Is Mediated by TNF-\u03b1 but Independent of Kupffer Cells"],"prefix":"10.1093","volume":"175","author":[{"given":"Markus","family":"Biburger","sequence":"first","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg , Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisa","family":"Tiegs","sequence":"additional","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg , Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2005,8,1]]},"reference":[{"key":"2026020214042397500_R1","first-page":"1472","volume-title":"J. 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