Impact of Fli-1 transcription factor on autoantibody and lupus nephritis in NZM2410 mice.
The transcription factor Fli-1 is implicated in the pathogenesis of both murine and human lupus. Increased levels of Fli-1 mRNA were present in the peripheral blood lymphocytes from lupus patients; furthermore, transgenic overexpression of Fli-1 in normal mice resulted in the development of a lupus-like disease. Lupus nephritis is a major cause of death in both lupus patients as well as in animal models. In this study, we generated Fli-1 heterozygous knockout (Fli-1(+/)⁻ ) NZM2410 mice (of which the wild-type is a widely used lupus murine model) that expressed decreased levels of Fli-1 and investigated the impact of Fli-1 expression on lupus nephritis development and survival. Ninety-three per cent of the Fli-1(+/)⁻ NZM2410 mice survived to the age of 52 weeks compared to only 35% of wild-type NZM2410 mice. Autoantibodies, including anti-dsDNA and anti-glomerular basement antigen, in Fli-1(+/)⁻ NZM2410 mice were statistically significantly lower when compared to wild-type NZM2410 mice at the ages of 30 and 34 weeks. Total B cell and activated B cell populations in the spleens from Fli-1(+/)⁻ NZM2410 mice were decreased significantly compared to wild-type NZM2410 mice. Fli-1(+/)⁻ NZM2410 mice also had remarkably diminished proteinuria and decreased renal pathological scores when compared with wild-type NZM2410 mice. Expression of early growth response 1 (Egr-1) was decreased significantly in the kidneys from Fli-1(+/)⁻ NZM2410 mice when compared to wild-type littermates. Our data indicate that expression of Fli-1 plays an important role in lupus disease development in NZM2410 mice.
Mathenia
J
J
Department of Medicine, Medical University of South Carolina, USA.
Reyes-Cortes
E
E
Williams
S
S
Molano
I
I
Ruiz
P
P
Watson
D K
DK
Gilkeson
G S
GS
Zhang
X K
XK
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000917:Antibody Formation / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002452:Cell Count; D051766:Early Growth Response Protein 1 / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics; D007074:Immunoglobulin G / Q000097:blood; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000652:urine; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D011507:Proteinuria / Q000652:urine; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C497426:Fli1 protein, mouse; D007074:Immunoglobulin G; D051789:Proto-Oncogene Protein c-fli-1; C051951:antiglomerular basement membrane antibody