Parenchymal, but not leukocyte, TNF receptor 2 mediates T cell-dependent hepatitis in mice.
TNF-alpha is a central mediator of T cell activation-induced hepatitis in mice, e.g., induced by Pseudomonas exotoxin A (PEA). In this in vivo mouse model of T cell-dependent hepatitis, liver injury depends on both TNFRs. Whereas TNFR1 can directly mediate hepatocyte death, the in vivo functions of TNFR2 in pathophysiology remained unclear. TNFR2 has been implicated in deleterious leukocyte activation in a transgenic mouse model and in enhancement of TNFR1-mediated cell death in cell lines. In this study, we clarify the role of hepatocyte- vs leukocyte-expressed TNFR2 in T cell-dependent liver injury in vivo, using the PEA-induced hepatitis model. Several types of TNFR2-expressing leukocytes, especially neutrophils and NK cells, accumulated within the liver throughout the pathogenic process. Surprisingly, only parenchymal TNFR2 expression, but not the TNFR2 expression on leukocytes, contributed to PEA-induced hepatitis, as shown by analysis of wild-type --> tnfr2 degrees and the reciprocal mouse bone marrow chimeras. Furthermore, PEA induced NF-kappaB activation and cytokine production in the livers of both wild-type and tnfr2 degrees mice, whereas only primary mouse hepatocytes from wild-type, but not from tnfr2 degrees, mice were susceptible to cell death induced by a combination of agonistic anti-TNFR1 and anti-TNFR2 Abs. Our results suggest that parenchymal, but not leukocyte, TNFR2 mediates T cell-dependent hepatitis in vivo. The activation of leukocytes does not appear to be disturbed by the absence of TNFR2.
Schümann
Jens
J
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Fahrstrasse 17, DE-91054 Erlangen, Germany.
Mühlen
Katrin
K
Kiemer
Alexandra K
AK
Vollmar
Angelika M
AM
Tiegs
Gisa
G
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000097:blood / Q000502:physiology* / Q000528:radiation effects; D001426:Bacterial Proteins / Q000633:toxicity; D001854:Bone Marrow Cells / Q000276:immunology / Q000528:radiation effects; D016026:Bone Marrow Transplantation; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism*; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000096:biosynthesis; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism; D017708:Leukocyte Transfusion; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism* / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D011828:Radiation Chimera; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000097:blood / Q000502:physiology* / Q000528:radiation effects; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D015703:Antigens, CD; D001426:Bacterial Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; C111749:pseudomonas exoprotein A protein, Pseudomonas aeruginosa