Correlation of Interleukin-6 and monocyte chemotactic protein-1 levels with the crescent formation and myeloperoxidase-specific anti-neutrophil cytoplasmic antibody titer in SCG/Kj mice by treatment with anti-interleukin-6 receptor antibody or Mizoribine
ABSTRACT Myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA) associates with rapidly progressive glomerulonephritis (RPGN) and glomerular crescent formation. We analyzed pathogenic factors of RPGN by using SCG/Kj mice, which spontaneously develop MPO-ANCA-associated RPGN. Serum concentration of soluble IL-6R (sIL-6R) was determined by using ELISA and other 23 cytokines and chemokines in serum were determined by Bio-Plex analysis. Sections of frozen kidney tissues were examined under a fluorescence microscope and the CD3(+) B220(+) T cell subset in spleen was determined by a flow cytometry. IL-6 and monocyte chemotactic protein-1 (MCP-1) were significantly correlated with the percentages of crescent formation. We administered anti-IL-6R antibody, which has been effective in patients with rheumatoid arthritis, to SCG/Kj mice to elucidate the role of IL-6 in the development of RPGN. MPO-ANCA titer decreased after administration of anti-IL-6R antibody, but not that of Mizoribine which is effective on Kawasaki disease model mice. These results suggest that IL-6-mediated signaling is involved in the production of MPO-ANCA.
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ABSTRACT: Background The spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mouse, a model of human crescentic glomerulonephritis (CrGN) and systemic vasculitis, is characterized by the production of MPO-ANCA and marked leukocytosis. This study was performed to identify the specific populations of leukocytes associated with CrGN and susceptibility loci for pathogenic leukocytosis.Methods420 female (C57BL/6 × SCG/Kj) F2 intercross mice were subjected to serial flow cytometry examination of the peripheral blood (PB). Kidney granulocytes and monocytes were histopathologically examined. Linkage analyses were done with 109 polymorphic microsatellite markers.ResultsCorrelation studies revealed that increase of the granulocytes, F4/80+ cells, CD3+CD4-CD8- T cells, and dendritic cells (DCs) in PB were significantly associated with glomerulonephritis, crescent formation and vasculitis. In kidney sections, F4/80low cells were observed in crescent, while F4/80high cells were around the Bowman's capsules and in the interstitium. Numbers of F4/80+ cells in crescents significantly correlated with F4/80+ cell numbers in PB, but not with numbers of F4/80+ cells in the interstitium. Genome-wide quantitative trait locus (QTL) mapping revealed three SCG/Kj-derived non-Fas QTLs for leukocytosis, two on chromosome 1 and one on chromosome 17. QTLs on chromosome 1 affected DCs, granulocytes and F4/80+ cells, but QTL on chromosome 17 affected DCs and granulocytes.Conclusion We found CrGN-associated leukocytes and susceptibility QTLs with their positional candidate genes. F4/80+ cells in crescents are considered as recruited inflammatory macrophages. The results provide information for leukocytes to be targeted and genetic elements in CrGN and vasculitis.Clinical & Experimental Immunology 03/2014; 177(1). DOI:10.1111/cei.12333 · 3.28 Impact Factor