title: Dendritic cell maturation stage determines susceptibility to the proteasome inhibitor bortezomib.
abstract: The proteasome inhibitor bortezomib has been used successfully in the treatment of non-Hodgkin lymphomas in humans, and in the treatment of graft versus host disease (GVHD) and autoimmune diseases in animal models. The mechanism of growth inhibition and immunosuppression is only partly understood. Here, we have evaluated the differential effect of bortezomib on human monocyte derived immature and mature dendritic cells (DCs) as the maturation stage of DCs determines their function. We found bortezomib to induce apoptotic cell death in immature DCs and to a much lesser extent, in mature DCs. Furthermore, cytokine-induced maturation of immature DCs was inhibited by bortezomib, whereas already matured DCs remained unaffected as seen by phenotype and allo-stimulatory capacity. This corresponded to a decreased NF-kappaB activity in immature DCs, whereas NF-kappaB activity of mature DCs was not affected. In conclusion, our data expand on previous reports on the effects of proteasome inhibitors on human monocyte-derived DCs by demonstrating a differential effect of bortezomib on immature versus mature DCs. Our findings suggest a potential role of bortezomib in modulating immune responses in humans through inhibition of DC maturation.
authors.affiliation: Charité, Universitaetsmedizin Berlin, Campus Virchow Klinikum, Med. Klinik m. S. Haematologie/Onkologie, Berlin, Germany. marion.subklewe@charite.de
authors.forename: Marion
authors.initials: M
authors.lastname: Subklewe
authors.forename: Kathrin
authors.initials: K
authors.lastname: Sebelin-Wulf
authors.forename: Carola
authors.initials: C
authors.lastname: Beier
authors.forename: Andreas
authors.initials: A
authors.lastname: Lietz
authors.forename: Stephan
authors.initials: S
authors.lastname: Mathas
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Antonio
authors.initials: A
authors.lastname: Pezzutto
mesh_terms: D000328:Adult; D017951:Antigen Presentation / Q000187:drug effects*; D015703:Antigens, CD / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D024202:Electrophoretic Mobility Shift Assay; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D016130:Immunophenotyping; D015847:Interleukin-4 / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D015847:Interleukin-4; D000069286:Bortezomib; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D046988:Proteasome Endopeptidase Complex