Alpha-galactosylceramide-induced liver injury in mice is mediated by TNF-alpha but independent of Kupffer cells.
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Alpha-galactosylceramide-induced liver injury in mice is mediated by TNF-alpha but independent of Kupffer cells. / Biburger, Markus; Tiegs, Gisa.
in: J IMMUNOL, Jahrgang 175, Nr. 3, 3, 2005, S. 1540-1550.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Alpha-galactosylceramide-induced liver injury in mice is mediated by TNF-alpha but independent of Kupffer cells.
AU - Biburger, Markus
AU - Tiegs, Gisa
PY - 2005
Y1 - 2005
N2 - 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 Valpha14 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.
AB - 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 Valpha14 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.
KW - Animals
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Genetic Predisposition to Disease
KW - Species Specificity
KW - Enzyme Activation
KW - Injections, Intravenous
KW - Caspases/metabolism
KW - Caspase 3
KW - Cytokines/biosynthesis
KW - Drug-Induced Liver Injury/enzymology/genetics/immunology/pathology
KW - Galactosylceramides/administration & dosage/toxicity
KW - Killer Cells, Natural/immunology/metabolism/pathology
KW - Kupffer Cells/immunology/metabolism/pathology
KW - T-Lymphocyte Subsets/immunology/metabolism/pathology
KW - Tumor Necrosis Factor-alpha/biosynthesis/physiology
KW - Animals
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Genetic Predisposition to Disease
KW - Species Specificity
KW - Enzyme Activation
KW - Injections, Intravenous
KW - Caspases/metabolism
KW - Caspase 3
KW - Cytokines/biosynthesis
KW - Drug-Induced Liver Injury/enzymology/genetics/immunology/pathology
KW - Galactosylceramides/administration & dosage/toxicity
KW - Killer Cells, Natural/immunology/metabolism/pathology
KW - Kupffer Cells/immunology/metabolism/pathology
KW - T-Lymphocyte Subsets/immunology/metabolism/pathology
KW - Tumor Necrosis Factor-alpha/biosynthesis/physiology
M3 - SCORING: Journal article
VL - 175
SP - 1540
EP - 1550
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 3
M1 - 3
ER -
