Binding of anti-dsDNA antibodies to proximal tubular epithelial cells contributes to renal tubulointerstitial inflammation.

Susan Yung, Claudia Y C Ng, Kin Yi Au, Kwok Fan Cheung, Qing Zhang, Chenzhu Zhang, Desmond Y H Yap, Mel K M Chau, Tak Mao Chan

Clinical science (London, England : 1979) 2017 Jan 01

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Immune deposits are often observed along the tubular basement membrane in patients with lupus nephritis, but the role of anti-dsDNA antibody (Ab) deposition on tubulointerstitial inflammation remains to be investigated. We examined the effect of human polyclonal anti-dsDNA Abs on inflammatory processes in cultured proximal renal tubular epithelial cells (PTEC, HK-2 cells) and their association with serum levels of interleukin (IL)-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1) in patients. Binding of anti-dsDNA Abs to HK-2 cells was investigated by cellular ELISA, flow cytometry and immunohistochemistry. IL-6, IL-8 and MCP-1 secretion, mitogen-activated protein kinase (MAPK) activation and the effect of mycophenolic acid (MPA) were investigated by ELISAs and Western blot analysis. NZBWF1/J mice with active nephritis were randomized to receive either mycophenolate mofetil (MMF) (100 mg/kg per day) or vehicle for up to 12 weeks to study renal histopathology focusing on tubulointerstitial changes. Our results demonstrated that anti-dsDNA Abs bound to HK-2 cell surface and induced IL-6, IL-8 and MCP-1 secretion through distinct MAPK pathways. MPA inhibited anti-dsDNA Ab binding to HK-2 cells and suppressed apical and basolateral IL-6 and IL-8, but not MCP-1, secretion. Anti-dsDNA Ab level correlated with serum and tubulointerstitial expression of IL-6, IL-8 and MCP-1. MMF treatment in NZBWF1/J mice reduced anti-dsDNA Ab production and MAPK activation in the renal tubulointerstitium, together with decreased IL-6 and MCP-1 expression. Our data demonstrate that anti-dsDNA Abs contribute to inflammatory processes in the tubulointerstitium in lupus nephritis through their binding to proximal renal tubular epithelial cells and induction of pro-inflammatory mediators, and MPA ameliorates anti-dsDNA Ab induced IL-6 and IL-8 secretion in these cells. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Citation

Susan Yung, Claudia Y C Ng, Kin Yi Au, Kwok Fan Cheung, Qing Zhang, Chenzhu Zhang, Desmond Y H Yap, Mel K M Chau, Tak Mao Chan. Binding of anti-dsDNA antibodies to proximal tubular epithelial cells contributes to renal tubulointerstitial inflammation. Clinical science (London, England : 1979). 2017 Jan 01;131(1):49-67