Binding of Anti-dsDNA Antibodies to Proximal Tubular Epithelial Cells Contributes to Renal Tubulo-interstitial Inflammation

We examined the effect of human polyclonal anti-dsDNA antibodies on inflammatory processes in cultured proximal renal tubular epithelial cells (HK-2 cells) and their association with serum levels of IL-6, IL-8 and MCP-1 in patients. Binding of anti-dsDNA antibodies to HK-2 cells was investigated by cellular ELISA, flow cytometry and immunohistochemistry. IL-6, IL-8 and MCP-1 secretion, 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 MMF (100 mg/kg/day) or vehicle for up to 12 weeks to study renal histopathology focusing on tubulo-interstitial changes. Our results demonstrated that anti-dsDNA antibodies bound to HK-2 cell surface and induced IL-6, IL-8 and MCP-1 secretion through distinct MAPK pathways. MPA inhibited anti-dsDNA antibody binding to HK-2 cells and suppressed apical and basolateral IL-6 and IL-8, but not MCP-1, secretion. Anti-dsDNA antibody level correlated with serum and tubulo-interstitial expression of IL-6, IL-8 and MCP-1. MMF treatment in NZBWF1/J mice reduced anti-dsDNA antibody production and MAPK activation in the renal tubulo-interstitium, together with decreased IL-6 and MCP-1 expression. Our data demonstrate that anti-dsDNA antibodies contribute to inflammatory processes in the tubulo-interstitium in lupus nephritis through their binding to proximal tubular epithelial cells and induction of pro-inflammatory mediators, ...

Source: Clinical Science - October 24, 2016 Category: Biomedical Science Authors: Yung, S., Ng, C. Y., Au, K. Y., Cheung, K. F., Zhang, Q., Zhang, C., Yap, D. Y., Chau, M. K., Chan, T. M. Tags: PublishAheadOfPrint Source Type: research