Correlation of interleukin‐6 and monocyte chemotactic protein‐1 concentrations with 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) is associated with rapidly progressive glomerulonephritis (RPGN) and glomerular crescent formation. Pathogenic factors in RPGN were analyzed by using SCG/Kj mice, which spontaneously develop MPO-ANCA-associated RPGN. The serum concentration of soluble IL-6R was determined by using ELISA and those of another 23 cytokines and chemokines by Bio-Plex analysis. Sections of frozen kidney tissue were examined by fluorescence microscopy and the CD3 þ B220 þ T cell subset in the spleen determined by a flow cytometry. Concentrations of IL-6 and monocyte chemotactic protein-1 were significantly correlated with the percentages of crescent formation. Anti-IL-6R antibody, which has been effective in patients with rheumatoid arthritis, was administered to SCG/Kj mice to elucidate the role of IL-6 in the development of RPGN. MPO-ANCA titers decreased after administration of anti-IL-6R antibody, but not titers of mizoribine, which is effective in Kawasaki disease model mice. These results suggest that IL-6-mediated signaling is involved in the production of MPO-ANCA.

The association of serum interleukin-6 levels with clinical outcomes in antineutrophil cytoplasmic antibody-associated vasculitis

“…The associations of sIL-6 with pulmonary granulomatous manifestations of AAV and PR3-ANCA serology observed in this human study contrast with the results of most preclinical studies, which showed sIL-6 involvement associated with MPO-ANCA and rapidly progressive glomerulonephritis [19,20]. This apparent contradiction may be partially explained by the fact that there is no established model of PR3-ANCA associated granulomatous inflammation in GPA/PR3-AAV, making a comparison between humans and mice difficult.…”

“…Small case series or case reports have described elevated IL-6 levels in blood of patients with ANCA-associated vasculitis (AAV) and its local production at sites of active vasculitis, leading investigators to postulate a role of IL-6 in the pathogenesis of AAV [12][13][14][15][16][17][18]. Studies in a mouse model of myeloperoxidase (MPO)-ANCA-associated rapidly progressive glomerulonephritis suggested that IL-6-mediated signaling may increase the severity of disease [19], and be involved in ANCA production [20]. Exploratory analyses have shown that levels of circulating IL-6 and other cytokines are elevated in patients with severe active AAV [21,22].…”

Clinical outcomes and clinico-pathological correlations in children with MPO-ANCA-associated glomerulonephritis showing renal arteritis

“…High levels of IL-6 were linked to inflammatory and antibody-related autoimmune disease, 29 and the signaling pathway mediated by IL-6 has been implicated in the exacerbation of disease severity 30 and may play a role in the production of ANCA. 31 The findings of our study demonstrate that arteritis was not solely associated with inflammatory factors, but also strongly correlated with interstitial inflammation and tubulitis. This suggested that arteritis may occur in the early stages of AAGN, and that both inflammatory responses and renal inflammatory response may be involved in the formation of arteritis.…”

Molecular targeted therapies for microscopic polyangiitis and granulomatosis with polyangiitis

“…Interleukin-6 (IL-6) is a pleotropic inflammatory cytokine that is also involved in the pathogenesis of AAV. Nagao et al [32] found a significant association between the serum concentration of IL-6 and glomerular crescent formation in SCG/Kj mice, an animal model of MPA. Treatment of the mice with anti-IL-6-receptor antibody significantly decreased serum titers of MPO-ANCA and tended to improve proteinuria and hematuria.…”