Differential contribution of IL-4 and STAT6 vs STAT4 to the development of lupus nephritis.
Mechanisms that initiate lupus nephritis and cause progression to end-stage renal disease remain poorly understood. In this study, we show that lupus-prone New Zealand Mixed 2410 mice that develop a severe glomerulosclerosis and rapidly progressive renal disease overexpress IL-4 in vivo. In these mice, STAT6 deficiency or anti-IL-4 Ab treatment decreases type 2 cytokine responses and ameliorates kidney disease, particularly glomerulosclerosis, despite the presence of high levels of IgG anti-dsDNA Abs. STAT4 deficiency, however, decreases type 1 and increases type 2 cytokine responses, and accelerates nephritis, in the absence of high levels of IgG anti-dsDNA Abs. Thus, STAT6 and IL-4 may selectively contribute to the development of glomerulosclerosis, whereas STAT4 may play a role in autoantibody production.
Singh
Ram Raj
RR
University of Cincinnati College of Medicine, Department of Internal Medicine, Veterans Affairs Medical Center and Children's Medical Center, Cincinnati, OH 45220, USA.
Saxena
Vijay
V
Zang
Song
S
Li
Lily
L
Finkelman
Fred D
FD
Witte
David P
DP
Jacob
Chaim O
CO
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007274:Injections, Intraperitoneal; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013045:Species Specificity; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4