Importance of Kupffer cells for T-cell-dependent liver injury in mice.
T cells seem to be responsible for liver damage in any type of acute hepatitis. Nevertheless, the importance of Kupffer cells (KCs) for T-cell-dependent liver failure is unclear. Here we focus on the role of KCs and tumor necrosis factor (TNF) production after T cell stimulation in mice. T-cell- and TNF-dependent liver injury were induced either by Pseudomonas exotoxin A (PEA), by concanavalin A (Con A), or by the combination of subtoxic doses of PEA and the superantigen Staphylococcus enterotoxin B (SEB). KCs were depleted by clodronate liposomes. Although livers of PEA-treated mice contained foci of confluent necrosis and numerous apoptotic cells, hardly any apoptotic cells were observed in the livers of Con A-treated mice. Instead, large bridging necroses were visible. Elimination of KCs protected mice from PEA-, Con A-, or PEA/SEB-induced liver injury. In the absence of KCs, liver damage was restricted to a few small necrotic areas. KCs were the main source of TNF. Hepatic TNF mRNA and protein production were strongly attenuated because of KC-depletion whereas plasma TNF levels were unaltered. Our results suggest that KCs play an important role in T cell activation-induced liver injury by contributing TNF. Plasma TNF levels are poor diagnostic markers for the severity of TNF-dependent liver inflammation.
Schümann
J
J
Institutes of Experimental and Clinical Pharmacology and Toxicology and Pathology, University of Erlangen-Nürnberg, Erlangen, Germany.
Wolf
D
D
Pahl
A
A
Brune
K
K
Papadopoulos
T
T
van Rooijen
N
N
Tiegs
G
G
D036002:ADP Ribose Transferases; D000818:Animals; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D056486:Chemical and Drug Induced Liver Injury; D003208:Concanavalin A; D004338:Drug Combinations; D004768:Enterotoxins; D005098:Exotoxins; D007728:Kupffer Cells / Q000502:physiology*; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D003208:Concanavalin A; D004338:Drug Combinations; D004768:Enterotoxins; D005098:Exotoxins; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C031818:enterotoxin B, staphylococcal