title: Stat1 Regulates Lupus-like Chronic Graft-versus-Host Disease Severity via Interactions with Stat3.
abstract: Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease, characterized by a spectrum of autoantibodies that target multiple cellular components. Glomerulonephritis is a major cause of morbidity in patients with SLE. Little is known about the pathogenesis of SLE renal damage and compromised renal function. Activation of both Stat1 and Stat3 has been reported in lupus and lupus nephritis. 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 lupus-like chronic graft-versus-host disease (cGVHD) in Stat1-knockout (KO) and wild-type (WT) mice by i.p. injection of class II-disparate bm12 splenocytes. 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 with WT mice (week 4 to week 8). Increased autoantibody titers were accompanied by increased proteinuria and mortality in the cGVHD host mice lacking Stat1. Further analysis revealed expression and activation of Stat3 in the glomeruli of Stat1-KO host mice but not WT mice with cGVHD. Glomerular Stat3 activity in the Stat1-KO mice was associated with increased IL-6 and IFN-γ secretion and macrophage infiltration. Interactions between Stat1 and Stat3 thus appear to be crucial in determining the severity of lupus-like disease in the cGVHD model.
authors.affiliation: Section of Rheumatology, Department of Medicine, Temple University, Philadelphia, PA 19140; and wshao@temple.edu.
authors.forename: Wen-Hai
authors.initials: WH
authors.lastname: Shao
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Temple University, Philadelphia, PA 19140.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gamero
authors.affiliation: Section of Rheumatology, Department of Medicine, Temple University, Philadelphia, PA 19140; and.
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Zhen
authors.affiliation: Section of Rheumatology, Department of Medicine, Temple University, Philadelphia, PA 19140; and.
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Lobue
authors.affiliation: Section of Rheumatology, Department of Medicine, Temple University, Philadelphia, PA 19140; and.
authors.forename: Stephen O
authors.initials: SO
authors.lastname: Priest
authors.affiliation: Section of Rheumatology, Department of Medicine, Temple University, Philadelphia, PA 19140; and.
authors.forename: Hazem J
authors.initials: HJ
authors.lastname: Albandar
authors.affiliation: Section of Rheumatology, Department of Medicine, Temple University, Philadelphia, PA 19140; and.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Cohen
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D006086:Graft vs Host Disease / Q000276:immunology*; D007371:Interferon-gamma / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism; D008181:Lupus Nephritis / Q000209:etiology* / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D050794:STAT1 Transcription Factor / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*
chemical_list: D001323:Autoantibodies; D015850:Interleukin-6; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D007371:Interferon-gamma