title: Binding of anti-dsDNA antibodies to proximal tubular epithelial cells contributes to renal tubulointerstitial inflammation.
abstract: 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.
authors: Department of Medicine, The University of Hong Kong, Hong Kong dtmchan@hku.hk ssyyung@hku.hk.
authors: Susan
authors: S
authors: Yung
authors: Department of Medicine, The University of Hong Kong, Hong Kong.
authors: Claudia Y C
authors: CY
authors: Ng
authors: Department of Medicine, The University of Hong Kong, Hong Kong.
authors: Kin Yi
authors: KY
authors: Au
authors: Department of Medicine, The University of Hong Kong, Hong Kong.
authors: Kwok Fan
authors: KF
authors: Cheung
authors: Department of Medicine, The University of Hong Kong, Hong Kong.
authors: Qing
authors: Q
authors: Zhang
authors: Department of Medicine, The University of Hong Kong, Hong Kong.
authors: Chenzhu
authors: C
authors: Zhang
authors: Department of Medicine, The University of Hong Kong, Hong Kong.
authors: Desmond Y H
authors: DY
authors: Yap
authors: Department of Medicine, The University of Hong Kong, Hong Kong.
authors: Mel K M
authors: MK
authors: Chau
authors: Department of Medicine, The University of Hong Kong, Hong Kong dtmchan@hku.hk ssyyung@hku.hk.
authors: Tak Mao
authors: TM
authors: Chan
mesh_terms: D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D004247:DNA / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D007687:Kidney Tubules, Proximal / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology
chemical_list: D001323:Autoantibodies; D015850:Interleukin-6; D016209:Interleukin-8; D004247:DNA; D020928:Mitogen-Activated Protein Kinases
keywords: anti-dsDNA antibodies; cytokines; lupus nephritis; mitogen-activated protein kinase (MAPK); mycophenolic acid; proximal renal tubular epithelial cells