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.
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Masson staining of rat liver specimens. Please see pp. 159-168 for more information. Image provided by Xujiong Li.
Research Article|
December 09 2016
Binding of anti-dsDNA antibodies to proximal tubular epithelial cells contributes to renal tubulointerstitial inflammation
Susan Yung;
*Department of Medicine, The University of Hong Kong, Hong Kong
Correspondence: Professor Tak Mao Chan (email dtmchan@hku.hk) or Dr Susan Yung (email ssyyung@hku.hk)
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Claudia Y.C. Ng;
Claudia Y.C. Ng
*Department of Medicine, The University of Hong Kong, Hong Kong
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Kin Yi Au;
Kin Yi Au
*Department of Medicine, The University of Hong Kong, Hong Kong
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Kwok Fan Cheung;
Kwok Fan Cheung
*Department of Medicine, The University of Hong Kong, Hong Kong
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Qing Zhang;
Qing Zhang
*Department of Medicine, The University of Hong Kong, Hong Kong
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Chenzhu Zhang;
Chenzhu Zhang
*Department of Medicine, The University of Hong Kong, Hong Kong
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Desmond Y.H. Yap;
Desmond Y.H. Yap
*Department of Medicine, The University of Hong Kong, Hong Kong
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Mel K.M. Chau;
Mel K.M. Chau
*Department of Medicine, The University of Hong Kong, Hong Kong
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Tak Mao Chan
*Department of Medicine, The University of Hong Kong, Hong Kong
Correspondence: Professor Tak Mao Chan (email dtmchan@hku.hk) or Dr Susan Yung (email ssyyung@hku.hk)
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Publisher: Portland Press Ltd
Received:
June 04 2016
Revision Received:
September 30 2016
Accepted:
October 25 2016
Accepted Manuscript online:
October 25 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Clin Sci (Lond) (2017) 131 (1): 49–67.
Article history
Received:
June 04 2016
Revision Received:
September 30 2016
Accepted:
October 25 2016
Accepted Manuscript online:
October 25 2016
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. Clin Sci (Lond) 1 January 2017; 131 (1): 49–67. doi: https://doi.org/10.1042/CS20160421
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