title: Mice with defective Fas ligand are protected from crescentic glomerulonephritis.
abstract: Fas ligand is a well-known inducer of apoptosis in cells expressing its receptor Fas; it also prevents autoimmunity by inducing apoptosis of activated T cells. However, Fas ligand also mediates non-apoptotic functions involving inflammatory cell migration and cytokine responses. We sought here to study the role of Fas ligand in nephrotoxic nephritis, a model of crescentic glomerulonephritis, using generalized lymphoproliferative disorder (GLD) mice on a C57BL/6 background, which have defective Fas ligand and display only mild autoimmunity. These mice were significantly protected from glomerular crescent formation, glomerular thrombosis, renal impairment, and albuminuria 15 days after the induction of glomerulonephritis in comparison with wild-type mice. There were a reduced number of apoptotic cells in the glomeruli of nephritic GLD mice but no defect in their antibody responses or splenocyte proliferation at 15 days following the induction of glomerulonephritis. Bone marrow transplantation from wild-type mice restored disease susceptibility to GLD mice; however, wild-type mice were not protected when transplanted with bone marrow from GLD mice. Mesangial cells express Fas ligand in vitro, and these cells isolated from GLD mice produced lower amounts of monocyte chemoattractive protein-1 following interleukin-1 stimulation compared with cells from wild-type mice. Thus, Fas ligand-defective mice are protected from nephrotoxic nephritis, a disease in which both circulating and intrinsic renal cells appear to have a role.
authors.affiliation: Renal Section, Department of Medicine, Hammersmith Campus, Imperial College London, London, UK. r.tarzi@imperial.ac.uk
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Tarzi
authors.forename: Phoebe E H
authors.initials: PE
authors.lastname: Sharp
authors.forename: John P
authors.initials: JP
authors.lastname: McDaid
authors.forename: Liliane
authors.initials: L
authors.lastname: Fossati-Jimack
authors.forename: Paul E
authors.initials: PE
authors.lastname: Herbert
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Warrens
mesh_terms: D000419:Albuminuria / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics* / Q000378:metabolism*; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007136:Immunoglobulins; D000922:Immunotoxins; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism*; D013927:Thrombosis / Q000235:genetics
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007136:Immunoglobulins; D000922:Immunotoxins; D012333:RNA, Messenger