Parenchymal, but not leukocyte, TNF receptor 2 mediates T cell-dependent hepatitis in mice.
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Parenchymal, but not leukocyte, TNF receptor 2 mediates T cell-dependent hepatitis in mice. / Schümann, Jens; Mühlen, Katrin; Kiemer, Alexandra K; Vollmar, Angelika M; Tiegs, Gisa.
in: J IMMUNOL, Jahrgang 170, Nr. 4, 4, 2003, S. 2129-2137.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Parenchymal, but not leukocyte, TNF receptor 2 mediates T cell-dependent hepatitis in mice.
AU - Schümann, Jens
AU - Mühlen, Katrin
AU - Kiemer, Alexandra K
AU - Vollmar, Angelika M
AU - Tiegs, Gisa
PY - 2003
Y1 - 2003
N2 - 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.
AB - 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.
KW - Animals
KW - Male
KW - Cells, Cultured
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Bone Marrow Transplantation
KW - NF-kappa B/metabolism
KW - Injections, Intravenous
KW - Cell Death/immunology
KW - Antigens, CD/biosynthesis/blood/physiology/radiation effects
KW - Bacterial Proteins/toxicity
KW - Bone Marrow Cells/immunology/radiation effects
KW - Drug-Induced Liver Injury/immunology/pathology/therapy
KW - Hepatocytes/immunology/metabolism
KW - Interleukin-6/biosynthesis
KW - Kupffer Cells/immunology/metabolism
KW - Leukocyte Transfusion
KW - Leukocytes/immunology/metabolism/radiation effects
KW - Radiation Chimera
KW - Receptors, Tumor Necrosis Factor/biosynthesis/blood/physiology/radiation effects
KW - Receptors, Tumor Necrosis Factor, Type II
KW - Signal Transduction/immunology
KW - T-Lymphocyte Subsets/immunology
KW - Tumor Necrosis Factor-alpha/biosynthesis
KW - Animals
KW - Male
KW - Cells, Cultured
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Bone Marrow Transplantation
KW - NF-kappa B/metabolism
KW - Injections, Intravenous
KW - Cell Death/immunology
KW - Antigens, CD/biosynthesis/blood/physiology/radiation effects
KW - Bacterial Proteins/toxicity
KW - Bone Marrow Cells/immunology/radiation effects
KW - Drug-Induced Liver Injury/immunology/pathology/therapy
KW - Hepatocytes/immunology/metabolism
KW - Interleukin-6/biosynthesis
KW - Kupffer Cells/immunology/metabolism
KW - Leukocyte Transfusion
KW - Leukocytes/immunology/metabolism/radiation effects
KW - Radiation Chimera
KW - Receptors, Tumor Necrosis Factor/biosynthesis/blood/physiology/radiation effects
KW - Receptors, Tumor Necrosis Factor, Type II
KW - Signal Transduction/immunology
KW - T-Lymphocyte Subsets/immunology
KW - Tumor Necrosis Factor-alpha/biosynthesis
M3 - SCORING: Journal article
VL - 170
SP - 2129
EP - 2137
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 4
M1 - 4
ER -