Regulation of Lupus Nephritis by Stat3

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder often accompanied by nephritis, causing considerable morbidity and mortality [1,2]. Increased expression of type I Interferon (IFN) and interferon-inducible genes are frequently observed in cells from SLE patients and is associated with disease activity [3]. Activation of the interferon signaling molecules, Stat1 and Stat3, has also been reported in SLE [4,5]. Their activation levels correlated with many forms of glomerulonephritis. The reciprocal activation of these two transcription factors may have a major impact on renal inflammation. To study the role of Stat1 in a lupus model, we induced SLE-like chronic graft-versus-host disease (cGVHD) in Stat1-KO and in WT mice by intraperitoneal injection of class II-disparate bm12 splenocytes [6]. WT recipients of these alloreactive cells developed anti-dsDNA autoantibodies starting at week 2 as expected, with a decline after week 4. In contrast, Stat1-KO hosts exhibited a prolonged and significant increase of anti-dsDNA autoantibody responses compared to WT mice (week 4 to week 8). Increased autoantibody titers were accompanied by increased proteinuria and mortality in the cGVHD host mice lacking Stat1. Enhanced expression and activation of Stat3 were observed in the glomeruli of Stat1-KO host mice but not WT mice with cGVHD. Interactions between Stat1 and Stat3 thus appear to be crucial in determining the severity of lupus-like disease in the cGVHD model [6].