Pathogenic effect of a cell-penetrating anti-dsDNA autoantibody through p38 signaling pathway and pro-inflammatory cytokine stimulation in mesangial cells |
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Authors: | Pavithra Pravinsagar Sun-Woo Im |
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Affiliation: | Department of Biomedical Sciences, Graduate School of Medicine and Department of Microbiology, School of Medicine, Ajou University, Suwon, Republic of Korea |
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Abstract: | 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-α, IL-6 and IL-1β 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. |
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Keywords: | Lupus nephritis anti-double stranded DNA autoantibody penetrating antibody pro-inflammatory cytokines signaling molecule p38 |
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