Abstract
The liver has an enormous capacity to regenerate in response to insults, but the cellular events and molecules involved in liver regeneration are not well defined. In this study, we report that ligands expressed on the surface of lymphocytes have a substantial effect on liver homeostasis. We demonstrate that a T cell-restricted ligand, homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for herpesvirus entry mediator on T cells (LIGHT), signaling through the lymphotoxin receptor (LTbetaR) expressed on mature hepatocytes induces massive hepatomegaly. Using genetic targeting and a receptor fusion protein, we further show that mice deficient in LTbetaR signaling have a severe defect in their ability to survive partial hepatectomy with marked liver damage and failure to initiate DNA synthesis after partial hepatectomy. We further show that mice deficient in a LTbetaR ligand, LTalpha, also show decreased ability to survive partial hepatectomy with similar levels of liver damage and decreased DNA synthesis. Therefore, our study has revealed an unexpected role of lymphocyte-restricted ligands and defined a new pathway in supporting liver regeneration.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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DNA Replication / genetics
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DNA Replication / immunology
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Dose-Response Relationship, Immunologic
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Hepatectomy
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Hepatocytes / immunology
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Hepatocytes / metabolism
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Hepatocytes / pathology
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Hepatomegaly / genetics
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Hepatomegaly / immunology
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Hepatomegaly / pathology
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Ligands
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Liver Regeneration / genetics
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Liver Regeneration / immunology*
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Lymphotoxin beta Receptor
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Male
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Membrane Proteins / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Receptors, Tumor Necrosis Factor / deficiency
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / physiology*
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Tumor Necrosis Factor Ligand Superfamily Member 14
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / physiology
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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Ligands
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Ltbr protein, mouse
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Lymphotoxin beta Receptor
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Membrane Proteins
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Receptors, Tumor Necrosis Factor
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Tnfsf14 protein, mouse
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Tumor Necrosis Factor Ligand Superfamily Member 14
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Tumor Necrosis Factor-alpha