Pathogenic effect of a cell-penetrating anti-dsDNA autoantibody through p38 signaling pathway and pro-inflammatory cytokine stimulation in mesangial cells

• Published in: Animal cells and systems Vol. 22; no. 1; pp. 45 - 53
• Main Authors: Pravinsagar, Pavithra, Im, Sun-Woo, Jang, Young-Ju
• Format: Journal Article
• Language: Korean
• Published: 2018
• Subjects: pro-inflammatory cytokines; Lupus nephritis; penetrating antibody; anti-double stranded DNA autoantibody; signaling molecule p38
• ISSN: 1976-8354; 2151-2485

A subset of anti-dsDNA autoantibodies (autoAbs), cell-penetrating Abs, may play a pathogenic role in lupus nephritis. However, the pathogenic role(s) of the Abs has not been well explored. In this study the pathological effects of a positively charged CDR3-VH-containing and cell-penetrating anti-dsDNA monoclonal mouse autoAb 2C10 immunoglobulin G (IgG) and its recombinant VH domain were investigated in a mouse mesangial cell line with respect to activation of signaling molecules and transcription of pro-inflammatory cytokines. The IgG and VH reduced cell viability in cytotoxicity assays and delayed cell cycle progress in flow cytometric analysis. Western blotting experiments showed that they activated p38, MAPKAPK-2, RSK-1, Bcl-2 and ATF-2 in the associated pathway; RSK-1 activation was regulated by p38; p38 also activated MAPKAPK-2 and ATF-2; MAPKAPK-2 regulated RSK-1 activation, and Bcl-2 was up-regulated by RSK-1. The IgG and VH remarkably stimulated the transcription of pro-inflammatory cytokines, TNF-${\alpha}$, IL-6 and IL-$1{\beta}$ And the transcription was regulated by p38 activation. These results indicate that the cell-penetrating autoAbs such as 2C10 may play a pathogenic role in mesangial cells mainly through activation of p38 signaling pathway in combination with the stimulation of pro-inflammatory cytokine production.