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SMAC Mimetic BV6 Induces Cell Death in Monocytes and Maturation of Monocyte-Derived Dendritic Cells

Please always quote using this URN: urn:nbn:de:bvb:20-opus-142415
  • Background: Compounds mimicking the inhibitory effect of SMAC / DIABLO on X-linked inhibitor of apoptosis (XIAP) have been developed with the aim to achieve sensitization for apoptosis of tumor cells resistant due to deregulated XIAP expression. It turned out that SMAC mimetics also have complex effects on the NF kappa B system and TNF signaling. In view of the overwhelming importance of the NF kappa B transcription factors in the immune system, we analyzed here the effects of the SMAC mimetic BV6 on immune cells. Principal Findings:Background: Compounds mimicking the inhibitory effect of SMAC / DIABLO on X-linked inhibitor of apoptosis (XIAP) have been developed with the aim to achieve sensitization for apoptosis of tumor cells resistant due to deregulated XIAP expression. It turned out that SMAC mimetics also have complex effects on the NF kappa B system and TNF signaling. In view of the overwhelming importance of the NF kappa B transcription factors in the immune system, we analyzed here the effects of the SMAC mimetic BV6 on immune cells. Principal Findings: BV6 induced apoptotic and necrotic cell death in monocytes while T-cells, dendritic cells and macrophages were largely protected against BV6-induced cell death. In immature dendritic cells BV6 treatment resulted in moderate activation of the classical NF kappa B pathway, but it also diminished the stronger NF kappa B-inducing effect of TNF and CD40L. Despite its inhibitory effect on TNF- and CD40L signaling, BV6 was able to trigger maturation of immature DCs as indicated by upregulation of CD83, CD86 and IL12. Significance: The demonstrated effects of SMAC mimetics on immune cells may complicate the development of tumor therapeutic concepts based on these compounds but also arise the possibility to exploit them for the development of immune stimulatory therapies.show moreshow less

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Metadaten
Author: Nicole Müller-Sienerth, Lena Dietz, Philipp Holtz, Markus Kapp, Götz Ulrich Grigoleit, Carsten Schmuck, Harald Wajant, Daniela Siegmund
URN:urn:nbn:de:bvb:20-opus-142415
Document Type:Journal article
Faculties:Medizinische Fakultät / Medizinische Klinik und Poliklinik II
Language:English
Parent Title (English):PLoS ONE
Year of Completion:2011
Volume:6
Issue:6
Pagenumber:e21556
Source:PLoS ONE 6(6): e21556. doi:10.1371/journal.pone.0021556
DOI:https://doi.org/10.1371/journal.pone.0021556
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:Alpha-dependent apoptosis; C-IAP1; CIAP1; Cancer; Caspase-8 activation; Complex; Kappa-B activation; Necrosis; RIP1; TRAF2
Release Date:2019/01/25
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung