期刊
FRONTIERS IN IMMUNOLOGY
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.02024
关键词
caspase-8; death receptors; CD95; TNFR1; TRAF1; TRAF2; TRAILR1; TRAILR2
类别
资金
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [WA 1025/30-1, WA 1025/31-1]
- DAAD
- German Research Foundation (DFG)
- University of Wuerzburg
Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) knockout (KO) cells were generated to investigate the role of TRAF2 in signaling by TNFR1 and the CD95-type death receptors (DRs) TRAILR1/2 and CD95. To prevent negative selection effects arising from the increased cell death sensitivity of TRAF2-deficient cells, cell lines were used for the generation of the TRAF2 KO variants that were protected from DR-induced apoptosis downstream of caspase-8 activation. As already described in the literature, TRAF2 KO cells displayed enhanced constitutive alternative NF kappa B signaling and reduced TNFR1-induced activation of the classical NF kappa B pathway. There was furthermore a significant but only partial reduction in CD95-type DR-induced upregulation of the proinflammatory NF kappa B-regulated cytokine interleukin-8 (IL8), which could be reversed by reexpression of TRAF2. In contrast, expression of the TRAF2-related TRAF1 protein failed to functionally restore TRAF2 deficiency. TRAF2 deficiency resulted furthermore in enhanced procaspase-8 processing by DRs, but this surprisingly came along with a reduction in net caspase-8 activity. In sum, our data argue for (i) a non-obligate promoting function of TRAF2 in proinflammatory DR signaling and (ii) a yet unrecognized stabilizing effect of TRAF2 on caspase-8 activity.
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