Pivotal role of Stat4 and Stat6 in the pathogenesis of the lupus-like disease in the New Zealand mixed 2328 mice.
We have developed novel genetically lupus-prone (NZB x NZW)F(1)-derived congenic New Zealand mixed (NZM) 2328 lines, which are either Stat4- or Stat6-deficient. Our studies show that the deficiency of Stat4 and Stat6 significantly alters the phenotype of the lupus-like disease in NZM 2328 congenic mice. Specifically, Stat4-deficient NZM mice develop accelerated nephritis and increased mortality in the absence of high levels of autoantibodies including anti-dsDNA Abs, and in the presence of relatively reduced levels of IFN-gamma. In contrast, Stat6-deficient NZM mice display a significant reduction in incidence of kidney disease, with a dramatic increase in survival, despite the presence of high levels of anti-dsDNA Abs. The lack of correlation between levels of these autoantibodies and kidney disease raises the question of the direct cause-effect relationships between the presence of autoantibodies and kidney disease. Furthermore, these results also question the apparent equation of the effect of Stat deficiency with loss of secretion or response to particular cytokines.
Jacob
Chaim O
CO
Department of Medicine, University of Southern California School of Medicine, Los Angeles, CA 90089, USA.
Zang
Song
S
Li
Lily
L
Ciobanu
Voicu
V
Quismorio
Frank
F
Mizutani
Akiei
A
Satoh
Minoru
M
Koss
Michael
M
D000818:Animals; D002478:Cells, Cultured; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D013045:Species Specificity; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D016207:Cytokines; D004268:DNA-Binding Proteins; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators