Journal of Clinical and Cellular Immunology
Open Access
ISSN: 2155-9899
ISSN: 2155-9899
Wen Qiu, Ganqian Zhu, Yongting Li, Chenhui Zhao, Fengxia He, Mengya Zhou, Lulu Wang, Dan Zhao, Yanlai Lu, Jing Zhang, Yu Liu, Tianyi Yu and Yingwei Wang
Nanjing Medical University, China
Scientific Tracks Abstracts: J Clin Cell Immunol
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 (Ser153/164/239) 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.
Wen Qiu is currently an Associate Professor at Department of Immunology of Nanjing Medical University. He is exploring the roles and mechanisms of complement especially C5b-9 in the induction of glomerular mesangial cell (GMC) apoptosis, inflammation and proliferation in rat Thy-1 nephritis as a widely used model of human mesangial proliferative glomerulonephritis (MsPGN) as well as the roles and mechanisms of IL-17 in astrocyte pathological changes in EAE mice. These include signal transduction, microRNA regulation, and transcriptional factor regulation. He is also exploring the effects of post-transcriptional regulation such as ubiquitination and acetylation on the activation of signaling molecules, transcription factors and histones.