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.
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-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-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-1 was found to be downregulated in kidneys of MRL-Fas(lpr) 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.


CONCLUSIONS
IL-6 is a strong promoter of lupus nephritis and may be a promising new therapeutic target in the treatment of human lupus nephritis.
Cash
Hannes
H
Department of Internal Medicine, Division of Rheumatology and Clinical Immunology, Johannes Gutenberg-University, Mainz, Germany.
Relle
Manfred
M
Menke
Julia
J
Brochhausen
Christoph
C
Jones
Simon A
SA
Topley
Nicholas
N
Galle
Peter R
PR
Schwarting
Andreas
A
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000172:deficiency* / Q000235:genetics; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008017:Life Expectancy; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D011507:Proteinuria / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D019014:fas Receptor / Q000276:immunology
D015415:Biomarkers; D015850:Interleukin-6; D019010:Vascular Cell Adhesion Molecule-1; D019014:fas Receptor; D016753:Interleukin-10; D007371:Interferon-gamma