Endothelial monocyte-activating polypeptide-II (EMAP-II), a proinflammatory cytokine with antiangiogenic properties, renders tumours sensitive to tumour necrosis factor-alpha (TNF) treatment. The exact mechanisms for this effect remain unclear. Here we show that human endothelial cells (EC) are insensitive to TNF-induced apoptosis but after a short pre-treatment with EMAP-II, EC quickly undergo TNF-induced apoptosis. We further analysed this EMAP-II pre-treatment effect and found no increase of TNF-R1 protein expression but rather an induction of TNF-R1 redistribution from Golgi storage pools to cell membranes. In addition, we observed EMAP-II induced mobilization and membrane expression of the TNF-R1-Associated Death Domain (TRADD) protein. Immunofluorescence co-staining experiments revealed that these two effects occurred at the same time in the same cell but TNF-R1 and TRADD were localized in different vesicles. These findings suggest that EMAP-II sensitises EC to apoptosis by facilitating TNF-R1 apoptotic signalling via TRADD mobilization and introduce a molecular and antiangiogenic explanation for the TNF sensitising properties of EMAP-II in tumours.

Additional Metadata
Keywords Apoptosis, EMAP-II, Endothelial cells, TNF-R1, TRADD
Persistent URL dx.doi.org/10.1007/s10495-006-0284-5, hdl.handle.net/1765/74025
Journal Apoptosis
Citation
van Horssen, R, Rens, J.A.P, Schipper, D, Eggermont, A.M.M, & ten Hagen, T.L.M. (2006). EMAP-II facilitates TNF-R1 apoptotic signalling in endothelial cells and induces TRADD mobilization. Apoptosis, 11(12), 2137–2145. doi:10.1007/s10495-006-0284-5