Abstract
It is unclear what roles TNF-α has in the development of autoimmune hepatitis (AIH) and whether AIH is responsive to anti-TNF-α. We recently developed a mouse model of fatal AIH that develops in PD-1-deficient mice thymectomized three days after birth, finding that CCR6-CCL20 axis-dependent migration of dysregulated splenic T cells is crucial to induce AIH. In this study, we show the indispensable role of TNF-α in the development of AIH. Administering anti-TNF-α prevented the induction, but treatment by anti-TNF-α after the induction did not suppress progression. Administering anti-TNF-α did not prevent splenic T-cell activation, but did suppress hepatic CCL20 expression. In contrast, administering anti-CCL20 suppressed AIH but not elevated serum TNF-α levels. TNF-α stimulation enhanced CCL20 expression in hepatocytes. These findings suggest that TNF-α is essential in the induction of AIH through upregulation of hepatic CCL20 expression, which allows migration of dysregulated splenic T cells.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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Antibodies, Neutralizing / immunology
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Antibodies, Neutralizing / pharmacology
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Cell Movement / drug effects
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Cell Movement / immunology
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Cells, Cultured
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Chemokine CCL20 / genetics
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Chemokine CCL20 / immunology*
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Chemokine CCL20 / metabolism
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Gene Expression / drug effects
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Hepatitis, Autoimmune / immunology*
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Hepatitis, Autoimmune / mortality
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Hepatitis, Autoimmune / prevention & control
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Hepatocytes / drug effects
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Hepatocytes / immunology
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Hepatocytes / metabolism
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Kaplan-Meier Estimate
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Liver / immunology*
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Liver / metabolism
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Programmed Cell Death 1 Receptor / deficiency
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Programmed Cell Death 1 Receptor / genetics
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Programmed Cell Death 1 Receptor / immunology
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Reverse Transcriptase Polymerase Chain Reaction
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Spleen / immunology
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Spleen / metabolism
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Survival Rate
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Thymectomy
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Tumor Necrosis Factor-alpha / blood
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Tumor Necrosis Factor-alpha / immunology*
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Tumor Necrosis Factor-alpha / metabolism
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Up-Regulation / drug effects
Substances
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Antibodies, Monoclonal
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Antibodies, Neutralizing
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CCL20 protein, mouse
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Chemokine CCL20
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Tumor Necrosis Factor-alpha