title: IFN-gamma receptor signaling is essential for the initiation, acceleration, and destruction of autoimmune kidney disease in MRL-Fas(lpr) mice.
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.
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: A
authors.initials: A
authors.lastname: Schwarting
authors.forename: T
authors.initials: T
authors.lastname: Wada
authors.forename: K
authors.initials: K
authors.lastname: Kinoshita
authors.forename: G
authors.initials: G
authors.lastname: Tesch
authors.forename: V R
authors.initials: VR
authors.lastname: Kelley
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000517:prevention & control; D016923:Cell Death; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000502:physiology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000517:prevention & control; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000097:blood / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr / Q000235:genetics / Q000276:immunology*; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D013163:Splenomegaly / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D016173:Macrophage Colony-Stimulating Factor; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000096743:Interferon gamma Receptor