Abstract
BackgroundLupus nephritis (LN) is a complex chronic autoimmune disease of unknown etiology characterized by loss of tolerance against several self-antigens. Cytokines are known to be central players in LN pathogenesis. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is one important pathway that mediates signal transduction of several cytokines. In this study, we examined the pathogenic role of this pathway and how CP-690,550 treatment influences LN outcome.MethodsSix-month-old NZB/NZWF1 mice were divided into two different treatment groups: (1) control animals given vehicle treatment, cyclophosphamide, and mycophenolate mofetil treatment as positive controls of the therapy and (2) mice treated with CP-690,550, a JAK3 inhibitor. Mice were treated for 12 weeks. We evaluated renal function, anti-double-stranded DNA (anti-dsDNA) antibody, renal histology changes, kidney complement and immunoglobulin G (IgG) deposits, T-cell and macrophage infiltration, kidney inflammatory gene expression, and circulating cytokine changes.ResultsCP-690,550 treatment significantly reduced proteinuria and improved renal function and histological lesions of the kidney. Compared with vehicle-treated animals, those undergoing CP-690,550 treatment showed significantly diminished anti-dsDNA antibody and complement component C3 and IgG deposition in glomeruli. We also observed a significant reduction of T-cell and macrophage infiltration. Kidney gene expression revealed a reduction in inflammatory cytokines and complement and related macrophage-attracting genes. Circulating inflammatory cytokines were also reduced with treatment.ConclusionsOn the basis of our results, we conclude that the JAK-STAT pathway is implicated in the progression of renal inflammation in NZB/WF1 mice and that targeting JAK3 with CP-690,550 is effective in slowing down the course of experimental LN. Thus, CP-690,550 could become a new therapeutic tool in LN and other autoimmune diseases.
Highlights
Lupus nephritis (LN) is a complex chronic autoimmune disease of unknown etiology characterized by loss of tolerance against several self-antigens
JAK3 inhibition prolongs survival and ameliorates renal function To examine the effects of a JAK3 inhibitor on advanced LN in mice, we treated 6-month-old NZB/WF1 female mice with overt renal disease with CP-690,550 and compared this treatment with mycophenolate mofetil (MMF) and CYP as standard therapies
CP-690,550 treatment significantly reduced the deposition of immunoglobulin G (IgG) and component 3 (C3) in the glomeruli, probably as a result of the inhibition of circulating autoantibodies, as reflected by the reduced anti-double-stranded DNA (dsDNA) serum levels in treated animals
Summary
Lupus nephritis (LN) is a complex chronic autoimmune disease of unknown etiology characterized by loss of tolerance against several self-antigens. Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disorder characterized by loss of tolerance against nuclear autoantigens, anti-double-stranded DNA (anti-dsDNA) antibody production, immune complex (IC) deposition, and leukocyte infiltration in many target organs, as well as activated B and T cells [1, 2]. It is well known that the cytokine milieu is integrally involved in the pathogenesis of autoimmune diseases [3, 4]. Multiple cytokines, such as interferons (IFNs), tumor necrosis factor (TNF)-α interleukin (IL)-6, IL-12, IL-10, and IL-17, are implicated in the initiation, progression, and development of LN. IL-17 amplifies the immune response by inducing the local production of chemokines and cytokines, recruiting neutrophils and monocytes, augmenting the production of autoantibodies, and aggravating the inflammation and damage of target organs [12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
