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Interleukin 6 (IL-6) deficiency delays lupus nephritis in MRL-faslpr mice: the IL-6 pathway as a new therapeutic target in treatment of autoimmune kidney disease in systemic lupus erythematosus

Cash, Hannes, Relle, Manfred, Menke, Julia, Brochhausen, Christoph, Jones, Simon Arnett, Topley, Nicholas, Galle, Peter R. and Schwarting, Andreas 2009. Interleukin 6 (IL-6) deficiency delays lupus nephritis in MRL-faslpr mice: the IL-6 pathway as a new therapeutic target in treatment of autoimmune kidney disease in systemic lupus erythematosus. The Journal of Rheumatology 37 (1) , pp. 60-70. 10.3899/jrheum.090194

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Abstract

Objective. To investigate the pathophysiological effect of interleukin 6 (IL-6) on lupus nephritis in MRL-Faslpr mice. Methods. We generated IL-6-deficient MRL-Faslpr mice using a backcross/intercross breeding scheme. Renal pathology was evaluated using immunohistochemistry detection for macrophages, lymphocytes, vascular cell adhesion molecule-1 (VCAM-1), and TUNEL (terminal deoxynucleotide transferase-mediated dUTP nick end-labeling) for apoptotic cells, and renal IgG and C3 deposition by immunofluorescence staining. Expression of inflammatory markers in the spleen was analyzed by quantitative real-time reverse transcription-polymerase chain reaction. Serum cytokine concentrations were detected by FACS analysis. Results. IL-6 deficiency was highly effective in prolonging survival and ameliorating the clinical, immunological, and histological indicators of murine systemic lupus erythematosus. During the study period of 6 months, MRL-Faslpr IL-6 −/− mice showed delayed onset of proteinuria and hematuria compared to IL-6-intact control mice. Survival rate was 100% in IL-6-deficient MRL-Faslpr mice and 25% in the control group at 6 months of age. The absence of IL-6 resulted in significant reduction of infiltrating macrophages in the kidney (p < 0.05), a decrease in renal IgG and C3 deposition, and a reduction of CD4+ and CD8+ lymphocytes. The parenchymal adhesion molecule VCAM-1 was found to be downregulated in kidneys of MRL-Faslpr IL-6 −/− compared to IL-6-intact mice. We found elevated serum levels of IL-10 and interferon-γ in IL-6-deficient mice, while splenic mRNA showed an overall downregulation of immunoregulatory genes. Conclusion. IL-6 is a strong promoter of lupus nephritis and may be a promising new therapeutic target in the treatment of human lupus nephritis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine
Uncontrolled Keywords: interleukin 6, systemic lupus erythematosus, lupus nephritis, knockout model, MRL-faslpr
Publisher: The Journal of Rheumatology
ISSN: 0315-162X
Funders: Deutsche Forschungsgemeinschaft Grant Schw 785/2-1, Stiftung Innovation Rheinland-Pfalz
Last Modified: 30 Jun 2017 02:28
URI: http://orca.cf.ac.uk/id/eprint/29582

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