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The journal of immunology : official journal of the American Association of Immunologists v.198 no.3, 2017년, pp.1104 - 1118   SCI SCIE
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Sublytic C5b-9 Induces Glomerular Mesangial Cell Apoptosis through the Cascade Pathway of MEKK2–p38 MAPK–IRF-1–TRADD–Caspase 8 in Rat Thy-1 Nephritis

Zhu, Ganqian (Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China ); Qiu, Wen (Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China ); Li, Yongting (Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China ); Zhao, Chenhui (Department of Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China ); He, Fengxia (and ); Zhou, Mengya (Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China ); Wang, Lulu (Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China ); Zhao, Dan (Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China ); Lu, Yanlai (Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China ); Zhang, Jing (Department of Immunology, Nanjing Medical University, Nanjing 210029, Jiangsu, Pe ); Liu, Yu ( ); Yu, Tianyi ( ); Wang, Yingwei ( );
  • 초록  

    The apoptosis of glomerular mesangial cells (GMCs) in the early phase of rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis (MsPGN), is primarily triggered by sublytic C5b-9. However, the mechanism of GMC apoptosis induced by sublytic C5b-9 remains unclear. In this study, we demonstrate that expressions of TNFR1-associated death domain–containing protein (TRADD) and IFN regulatory factor–1 (IRF-1) were simultaneously upregulated in the renal tissue of Thy-1N rats (in vivo) and in GMCs under sublytic C5b-9 stimulation (in vitro). In vitro, TRADD was confirmed to be a downstream gene of IRF-1, because IRF-1 could bind to TRADD gene promoter to promote its transcription, leading to caspase 8 activation and GMC apoptosis. Increased phosphorylation of p38 MAPK was verified to contribute to IRF-1 and TRADD production and caspase 8 activation, as well as to GMC apoptosis induced by sublytic C5b-9. Furthermore, phosphorylation of MEK kinase 2 (MEKK2) mediated p38 MAPK activation. More importantly, three sites (Ser 153/164/239 ) of MEKK2 phosphorylation were identified and demonstrated to be necessary for p38 MAPK activation. In addition, silencing of renal MEKK2, IRF-1, and TRADD genes or inhibition of p38 MAPK activation in vivo had obvious inhibitory effects on GMC apoptosis, secondary proliferation, and urinary protein secretion in rats with Thy-1N. Collectively, these findings indicate that the cascade axis of MEKK2–p38 MAPK–IRF-1–TRADD–caspase 8 may play an important role in GMC apoptosis following exposure to sublytic C5b-9 in rat Thy-1N.


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