Interferon regulatory factor-1 gene deletion decreases glomerulonephritis in MRL/lpr mice.
To investigate the role of interferon regulatory factor-1 (IRF-1) in the development of lupus nephritis, IRF-1(-/-) genotype mice were bred onto the MRL/lpJfas(lpr) (MRL/lpr) background. We examined kidney mesangial cell function and disease progression. Endpoints evaluated included inflammatory mediators, autoantibody production, immune complex deposition, renal pathology, T cell subset analysis, and duration of survival. Mesangial cells cultured from IRF-1(-/-) mice produced significantly lower levels of nitric oxide and IL-12 but not TNF-alpha when stimulated with LPS + IFN-gamma. IRF-1(-/-) mice showed less aggravated dermatitis compared to the wild-type mice. Anti-double-stranded DNA production and proteinuria were significantly decreased in IRF-1(-/-) mice compared to IRF-1(+/+) mice. IgG and C3 deposition as well as glomerulonephritis were decreased in IRF-1(-/-) mice at 26 wk of age compared to the IRF-1(+/+) mice. Splenic CD4- CD8- CD44+ T cells were decreased while CD4+ CD25+ T cells were increased in the IRF-1(-/-) mice when compared to IRF-1(+/+) mice. Survival rates (ED50) were 22 wk for IRF-1(+/+) mice and 45 wk for IRF-1(-/-) mice. These findings suggest an important role of IRF-1 in mediating renal disease in MRL/lpr mice.
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA. chreilly@vcom.vt.edu
Christopher M
CM
Reilly
Selen
S
Olgun
David
D
Goodwin
Robert M
RM
Gogal
Arben
A
Santo
Jason W
JW
Romesburg
S Ansar
SA
Ahmed
Gary S
GS
Gilkeson
D000818:Animals; D005434:Flow Cytometry; D005920:Glomerular Mesangium / Q000473:pathology; D005921:Glomerulonephritis / Q000209:etiology*; D007074:Immunoglobulin G / Q000097:blood / Q000145:classification; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis; D007668:Kidney / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008181:Lupus Nephritis / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D012333:RNA, Messenger / Q000032:analysis; D050794:STAT1 Transcription Factor / Q000032:analysis; D050378:T-Lymphocytes, Regulatory / Q000502:physiology
D007074:Immunoglobulin G; D050856:Interferon Regulatory Factor-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma