Studies on the Effect of Nuclear-penetrating Anti-dsDNA Autoantibody IgG and Recombinant VH Domain in Lupus Nephritis-associated Kidney Cells

Abstract

The aim of this study is to investigate the pathological impacts of the anti-dsDNA antibodies, that are basically causative factors in autoimmune diseases. The anti-dsDNA autoantibody 2C10 IgG and its recombinant fragment 2C10 VH domain were tested in the normal murine kidney mesangial cells (MES) and human cervical cancer cell (HeLa) to know the pathogenic aspect of these antibodies. It was observed that the 2C10 IgG and 2C10 VH domain penetrated into the target cells and reduced their cell proliferation and the penetrated autoantibodies simultaneously activated the signal molecules ERK1/2 and p38. Further observation revealed that 2C10 IgG and 2C10 VH persistently activated RSK-1 and upregulated BCL-2 expression. In mesangial cell line, the 2C10 IgG and 2C10 VH stimulated the transcription of pro-inflammatory genes TNF-α, IL-6 and IL-1β through ATF-2 activation enormously, but the same pattern was not observed in HeLa cells. The activation of these signal molecules was linked to the production of pro-inflammatory cytokines, because inhibition of the molecules suppressed the cytokine production. Collectively, the cell-and nuclear-penetrating autoantibodies 2C10 IgG and 2C10 VH seem to play a pathogenic role in mesangial cells through activation of p38, MAPKAPKK2, RSK-1, BCL-2 and ATF-2 and consequent production of pro-inflammatory cytokines.