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 ORCID: https://orcid.org/0000-0001-7297-9711, 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:	20 Oct 2022 08:47
URI:	https://orca.cardiff.ac.uk/id/eprint/29582

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