Role of sinusoidal endothelial cells of the liver in concanavalin A-induced hepatic injury in mice.

TY - JOUR

T1 - Role of sinusoidal endothelial cells of the liver in concanavalin A-induced hepatic injury in mice.

AU - Knolle, P A

AU - Gerken, G

AU - Loser, E

AU - Dienes, H P

AU - Gantner, F

AU - Tiegs, Gisa

AU - Meyer Zum Buschenfelde, K H

AU - Lohse, A W

PY - 1996

Y1 - 1996

N2 - CD4+ T lymphocytes have been identified as being responsible for organ damage in the murine model of experimental liver injury induced by intravenous injection of concanavalin A (Con A). Liver sinusoidal endothelial cells (SEC) and Kupffer's cells (KC) are among the first cells that come into contact with lymphocytes in the liver sinusoid. We aimed to investigate the respective role of these cell populations in the initial steps of T-cell-mediated liver injury in Con A-induced hepatitis. By electron microscopy, we could show that intravenously applied Con A bound predominantly to SEC but not to KC. KC depletion by gadolinium chloride treatment of mice did not result in protection from liver injury, indicating that KCs are not primarily involved in the generation of liver injury. We could show that a CD4+ T-cell line (LNC.2) displayed selective cytotoxicity toward SEC (>50%) but not KC (12%) or fibroblasts (5%) in the presence of Con A in vitro. Microscopic observation revealed that the SEC monolayer was rapidly destroyed by LnC2 in the presence of Con A. Specificity of the Con A-induced cytotoxicity was shown by the ability of a competitive ligand, methyl-alpha-D-mannopyranoside, to reduce T-cell-mediated cytotoxicity to SEC by more than 50%. Tumor necrosis factor alpha (TNF-alpha) was produced by LnC2 in high amounts after Con A stimulation (>6 ng/mL), but antiserum to TNF-alpha did not reduce LnC2-mediated cytotoxicity toward SEC. In conclusion, we could show for the first time that liver SECs have accessory function and are selectively destroyed by CD4+ T lymphocytes in the presence of Con A. We speculate that SEC damage is an early event in T-cell-mediated liver injury recruiting T lymphocytes from the sinusoidal circulation. Loss of the SEC barrier function then exposes underlying hepatocytes to further attack by activated T lymphocytes. These results offer a model of initiating events in T-cell-mediated liver diseases, such as viral or autoimmune hepatitis, and suggest an important role for sinusoidal endothelial cells.

AB - CD4+ T lymphocytes have been identified as being responsible for organ damage in the murine model of experimental liver injury induced by intravenous injection of concanavalin A (Con A). Liver sinusoidal endothelial cells (SEC) and Kupffer's cells (KC) are among the first cells that come into contact with lymphocytes in the liver sinusoid. We aimed to investigate the respective role of these cell populations in the initial steps of T-cell-mediated liver injury in Con A-induced hepatitis. By electron microscopy, we could show that intravenously applied Con A bound predominantly to SEC but not to KC. KC depletion by gadolinium chloride treatment of mice did not result in protection from liver injury, indicating that KCs are not primarily involved in the generation of liver injury. We could show that a CD4+ T-cell line (LNC.2) displayed selective cytotoxicity toward SEC (>50%) but not KC (12%) or fibroblasts (5%) in the presence of Con A in vitro. Microscopic observation revealed that the SEC monolayer was rapidly destroyed by LnC2 in the presence of Con A. Specificity of the Con A-induced cytotoxicity was shown by the ability of a competitive ligand, methyl-alpha-D-mannopyranoside, to reduce T-cell-mediated cytotoxicity to SEC by more than 50%. Tumor necrosis factor alpha (TNF-alpha) was produced by LnC2 in high amounts after Con A stimulation (>6 ng/mL), but antiserum to TNF-alpha did not reduce LnC2-mediated cytotoxicity toward SEC. In conclusion, we could show for the first time that liver SECs have accessory function and are selectively destroyed by CD4+ T lymphocytes in the presence of Con A. We speculate that SEC damage is an early event in T-cell-mediated liver injury recruiting T lymphocytes from the sinusoidal circulation. Loss of the SEC barrier function then exposes underlying hepatocytes to further attack by activated T lymphocytes. These results offer a model of initiating events in T-cell-mediated liver diseases, such as viral or autoimmune hepatitis, and suggest an important role for sinusoidal endothelial cells.

KW - Animals

KW - Female

KW - Mice

KW - Mice, Inbred BALB C

KW - Organ Specificity

KW - Injections, Intravenous

KW - Tumor Necrosis Factor-alpha/immunology/metabolism

KW - CD4-Positive T-Lymphocytes/immunology/metabolism

KW - Concanavalin A/administration & dosage/metabolism

KW - Endothelium/metabolism

KW - Fibroblasts/immunology

KW - Gadolinium/pharmacology

KW - Hepatic Encephalopathy/chemically induced/immunology/metabolism/pathology

KW - Kupffer Cells/drug effects

KW - T-Lymphocytes, Cytotoxic/immunology

KW - Animals

KW - Female

KW - Mice

KW - Mice, Inbred BALB C

KW - Organ Specificity

KW - Injections, Intravenous

KW - Tumor Necrosis Factor-alpha/immunology/metabolism

KW - CD4-Positive T-Lymphocytes/immunology/metabolism

KW - Concanavalin A/administration & dosage/metabolism

KW - Endothelium/metabolism

KW - Fibroblasts/immunology

KW - Gadolinium/pharmacology

KW - Hepatic Encephalopathy/chemically induced/immunology/metabolism/pathology

KW - Kupffer Cells/drug effects

KW - T-Lymphocytes, Cytotoxic/immunology

M3 - SCORING: Journal article

VL - 24

SP - 824

EP - 829

JO - HEPATOLOGY

JF - HEPATOLOGY

SN - 0270-9139

IS - 4

M1 - 4

ER -