title: SMAC mimetic BV6 induces cell death in monocytes and maturation of monocyte-derived dendritic cells.
abstract: 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 NFκB system and TNF signaling. In view of the overwhelming importance of the NFκB transcription factors in the immune system, we analyzed here the effects of the SMAC mimetic BV6 on immune cells.
  
  
  RESULTS
  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 NFκB pathway, but it also diminished the stronger NFκB-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.
  
  
  CONCLUSIONS
  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.
authors: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
authors: Nicole
authors: N
authors: Müller-Sienerth
authors: Lena
authors: L
authors: Dietz
authors: Philipp
authors: P
authors: Holtz
authors: Markus
authors: M
authors: Kapp
authors: Götz Ulrich
authors: GU
authors: Grigoleit
authors: Carsten
authors: C
authors: Schmuck
authors: Harald
authors: H
authors: Wajant
authors: Daniela
authors: D
authors: Siegmund
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000737:chemistry*; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D010455:Peptides