Abstract
CSF-1 and TNF-alpha in the kidney of MRL-Fas(lpr) mice are proximal events that precede and promote autoimmune lupus nephritis, while apoptosis of renal parenchymal cells is a feature of advanced human lupus nephritis. In the MRL-Fas(lpr) kidney, infiltrating T cells that secrete IFN-gamma are a hallmark of disease. To examine the impact of IFN-gamma on renal injury in MRL-Fas(lpr) mice, we constructed a IFN-gamma R-deficient strain. In MRL-Fas(lpr) mice lacking IFN-gamma R, circulating and intrarenal CSF-1 were absent, TNF-alpha was markedly reduced, survival was extended, lymphadenopathy and splenomegaly were prevented, and the kidneys remained protected from destruction. Mesangial cells (MC) that were signaled through the IFN-gamma R induced CSF-1 and TNF-alpha in MRL-Fas(lpr) mice. We detected a large number of apoptotic renal parenchymal cells in advanced nephritis and determined that signaling via the IFN-gamma R induces apoptosis of tubular epithelial cells (TEC), but not MC. By comparison, TNF-alpha induces apoptosis in MC, but not TEC, of the MRL-Fas(lpr) strain. Thus, IFN-gamma is directly and indirectly responsible for apoptosis of TEC and MC in MRL-Fas(lpr) mice, respectively. In conclusion, IFN-gamma R signaling is essential for the initiation (CSF-1), acceleration (CSF-1 and TNF-alpha), and apoptotic destruction of renal parenchymal cells in MRL-Fas(lpr) autoimmune kidney disease.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / immunology
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology*
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Autoimmune Diseases / mortality
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Autoimmune Diseases / pathology*
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Autoimmune Diseases / prevention & control
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Cell Death
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Down-Regulation / genetics
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Down-Regulation / immunology
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Epithelial Cells / immunology
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Epithelial Cells / pathology
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Glomerular Mesangium / metabolism
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Glomerular Mesangium / pathology
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Interferon gamma Receptor
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Interferon-gamma / physiology*
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Kidney / metabolism
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Kidney / pathology
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Kidney / physiopathology
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Kidney Function Tests
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Kidney Tubules / immunology
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Kidney Tubules / pathology
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Lupus Nephritis / genetics
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Lupus Nephritis / immunology*
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Lupus Nephritis / mortality
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Lupus Nephritis / pathology*
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Lupus Nephritis / prevention & control
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Lymphatic Diseases / genetics
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Lymphatic Diseases / immunology
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Lymphatic Diseases / prevention & control
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Macrophage Colony-Stimulating Factor / biosynthesis
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Macrophage Colony-Stimulating Factor / blood
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Macrophage Colony-Stimulating Factor / deficiency
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Macrophage Colony-Stimulating Factor / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Inbred MRL lpr / genetics
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Mice, Inbred MRL lpr / immunology*
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Mice, Inbred Strains
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Mice, Knockout
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Receptors, Interferon / deficiency
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Receptors, Interferon / genetics
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Signal Transduction / immunology*
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Splenomegaly / prevention & control
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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fas Receptor / genetics
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fas Receptor / immunology
Substances
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Receptors, Interferon
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Tumor Necrosis Factor-alpha
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fas Receptor
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Macrophage Colony-Stimulating Factor
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Interferon-gamma