Interleukin-6 trans-signaling exacerbates inflammation and renal pathology in lupus
- Author(s)
- Tsantikos, E; Maxwell, MJ; Putoczki, T; Ernst, M; Rose-John, S; Tarlinton, DM; Hibbs, ML;
- Details
- Publication Year 2013,Volume 65,Issue #10,Page 2691-2702
- Journal Title
- Arthritis and Rheumatism
- Publication Type
- Journal Article
- Abstract
- OBJECTIVE: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by the production of anti-nuclear antibodies (ANAs) leading to immune-complex (IC) deposition in kidneys and nephritis. Lyn tyrosine kinase is a regulator of antibody-mediated autoimmune disease, evidenced by studies in gene-targeted mice and suggested in SLE genome-wide association scans. Like SLE patients, Lyn-deficient mice have increased levels of interleukin-6 (IL-6), and deletion of IL-6 from Lyn-deficient mice abrogates inflammation, pathogenic autoantibodies and nephritis. In this study, we have assessed the role of IL-6 trans-signaling in autoimmune disease by overexpression of soluble gp130Fc (sgp130Fc). METHODS: The effect of over-expression of sgp130Fc on immune cell phenotypes was determined in young and aged disease-bearing mice by flow cytometry, and ANAs were measured by ELISA. Glomerulonephritis was assessed by histopathology, glomerular area measurements, blood urea nitrogen concentration and immunohistochemistry. Immunofluorescence defined renal IC and complement deposition. The acute-phase response was determined by quantitative real-time PCR. RESULTS: In contrast to removing IL-6, impaired IL-6 trans-signaling had little effect on many immune cell abnormalities in Lyn-/- mice. Pathogenic ANAs and IC deposition in kidney were also unaltered by sgp130Fc. However, sgp130Fc led to diminished macrophage expansion, reduced glomerular leukocyte infiltration, reduced complement fixation, significantly attenuated glomerulonephritis and improved renal function in Lyn-deficient mice. CONCLUSION: Our results reveal key roles for leukocytes, complement and the innate immune system in mediating glomerulonephritis and implicate IL-6 trans-signaling in this process. We suggest that targeting this pathway may be an effective adjunct to B cell depletion in SLE treatment. (c) 2013 American College of Rheumatology.
- Publisher
- WILEY
- Research Division(s)
- Immunology
- Publisher's Version
- https://doi.org/10.1002/art.38061
- Terms of Use/Rights Notice
- Copyright © 2013 by the American College of Rheumatology
Creation Date: 2014-01-16 03:45:54
Last Modified: 2014-12-03 10:28:33