Interleukin 6 (IL-6) Deficiency Delays Lupus Nephritis in MRL-Fas(lpr) Mice: The IL-6 Pathway as a New Therapeutic Target in Treatment of Autoimmune Kidney Disease in Systemic Lupus Erythematosus

Objective. To investigate the pathophysiological effect of interleukin 6 (IL-6) on lupus nephritis in MRL-Fas(lpr) mice. Methods. We generated IL-6-deficient MRL-Fas(lpr) mice using a backcross/intercross breeding scheme. Renal pathology was evaluated using immunohistochemistry detection for macrophages, lymphocytes, vascular cell adhesion molecule-1 (VCAM-I), 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-polymerise 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-Fas(lpr) 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-Fas(lpr) 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-I 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-gamma 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. (First Release Dec 1 2009; J Rheumatol 2010;37:60-70; doi:10.3899/jrheum.090194)