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Activation of TNFR2 sensitizes macrophages for TNFR1-mediated necroptosis

Please always quote using this URN: urn:nbn:de:bvb:20-opus-162317
  • Macrophages express TNFR1 as well as TNFR2 and are also major producers of tumor necrosis factor (TNF), especially upon contact with pathogen-associated molecular patterns. Consequently, TNF not only acts as a macrophage-derived effector molecule but also regulates the activity and viability of macrophages. Here, we investigated the individual contribution of TNFR1 and TNFR2 to TNF-induced cell death in macrophages. Exclusive stimulation of TNFR1 showed no cytotoxic effect whereas selective stimulation of TNFR2 displayed mild cytotoxicity.Macrophages express TNFR1 as well as TNFR2 and are also major producers of tumor necrosis factor (TNF), especially upon contact with pathogen-associated molecular patterns. Consequently, TNF not only acts as a macrophage-derived effector molecule but also regulates the activity and viability of macrophages. Here, we investigated the individual contribution of TNFR1 and TNFR2 to TNF-induced cell death in macrophages. Exclusive stimulation of TNFR1 showed no cytotoxic effect whereas selective stimulation of TNFR2 displayed mild cytotoxicity. Intriguingly, the latter was strongly enhanced by the caspase inhibitor zVAD-fmk. The strong cytotoxic activity of TNFR2 in the presence of zVAD-fmk was reversed by necrostatin-1, indicating necroptotic cell death. TNFR1- and TNF-deficient macrophages turned out to be resistant against TNFR2-induced cell death. In addition, the cIAP-depleting SMAC mimetic BV6 also enforced TNF/TNFR1-mediated necroptotic cell death in the presence of zVAD-fmk. In sum, our data suggest a model in which TNFR2 sensitizes macrophages for endogenous TNF-induced TNFR1-mediated necroptosis by the known ability of TNFR2 to interfere with the survival activity of TRAF2-cIAP1/2 complexes.show moreshow less

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Metadaten
Author: Daniela Siegmund, Juliane Kums, Martin Ehrenschwender, Harald Wajant
URN:urn:nbn:de:bvb:20-opus-162317
Document Type:Journal article
Faculties:Medizinische Fakultät / Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II)
Language:English
Parent Title (English):Cell Death & Disease
Year of Completion:2016
Volume:7
Pagenumber:e2375
Source:Cell Death and Disease (2016) 7, e2375; doi:10.1038/cddis.2016.285
DOI:https://doi.org/10.1038/cddis.2016.285
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=27899821
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 611 Menschliche Anatomie, Zytologie, Histologie
Tag:TNFR2
Release Date:2018/07/12
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International