Inhibition of the proteasome influences murine and human dendritic cell development in vitro and in vivo

Zinser, Elisabeth; Rößner, Susanne; Littmann, Leonie; Lüftenegger, Daniel; Schubert, Ulrich S.; Steinkasserer, Alexander

doi:10.1016/j.imbio.2009.06.018

Cited by 20 publications

(21 citation statements)

References 34 publications

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“…Other studies have shown that degradation of IkB and release of proinflammatory cytokines can be altered by proteasome inhibitors. 46 However, these proteasome inhibitors also activate the transcription factor AP-1, which is known to contribute to LPS-induced cytokines. 37 Our results show that upon treatment of LPS-stimulated BMDC with MLN4924, the MAPK/ERK pathway is unperturbed ( Figure 7D-E), suggesting that AP-1 activity is unaltered by neddylation inhibition.…”

Section: Discussionmentioning

confidence: 99%

Neddylation plays an important role in the regulation of murine and human dendritic cell function

Mathewson

Toubai

Kapeles

et al. 2013

Blood

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• There is a role for the posttranslational modification, neddylation, in regulation of immune responses mediated by dendritic cells.• A role for neddylation in NF-kB signaling in dendritic cells was identified.Posttranslational protein modifications (PTMs) are necessary for cells to function properly. The role of PTMs in regulating immune responses, specifically those mediated by dendritic cells (DCs), which are critical for both innate and adaptive immunity, is not well understood. Utilizing multiple but complementary approaches, we determined the role of an important but less understood type of PTM, namely, neddylation, in regulating DC functions. Inhibition of neddylation suppressed the release of proinflammatory cytokines by DCs in response to Toll-like receptor, nucleotide oligomerization domain-like receptor, and noninfectious CD40L stimulation. These effects were more profound than those mediated by the proteasome inhibitor bortezomib or a commonly used antiinflammatory agent, dexamethasone. Targeting neddylation also suppressed the ability of DCs to stimulate murine allogeneic T cells in vitro and in vivo and human allogeneic T-cell responses in vitro. Mechanistic studies demonstrated that inhibition of neddylation reduced both canonical and noncanonical nuclear factor-kB (NF-kB) activity. Neddylation inhibition prevented the degradation of inhibitor-kB and thus reduced the translocation and activation of NF-kB, but without perturbation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Thus, blocking neddylation could be a novel strategy for mitigating immune-mediated disease processes. (Blood. 2013;122(12):2062-2073

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Section: Discussionmentioning

confidence: 99%

Neddylation plays an important role in the regulation of murine and human dendritic cell function

Mathewson

Toubai

Kapeles

et al. 2013

Blood

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“…On the basis of the reports from the literature, we used 0.75 mg/kg body wt BTZ because this dosage was shown to significantly reduce short-and long-lived plasma cells, activate the terminal unfolded protein response, abrogate NF-B, and impair dendritic cell maturation and functions. 29,49,50 Future studies should explore reduced dosage protocols. This issue of adverse effects certainly needs close follow-up and clinicians need to be alert.…”

Section: Discussionmentioning

confidence: 99%

Myeloperoxidase-Specific Plasma Cell Depletion by Bortezomib Protects from Anti-Neutrophil Cytoplasmic Autoantibodies–Induced Glomerulonephritis

Bontscho

Schreiber

Manz

et al. 2011

Journal of the American Society of Nephrology

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Anti-neutrophil cytoplasmic autoantibodies (ANCA) cause vasculitis and necrotizing crescentic glomerulonephritis (NCGN). Steroids and cytotoxic drugs reduce mortality but can cause significant adverse events. The proteasome inhibitor bortezomib (BTZ) prevents glomerulonephritis in mouse models of lupus but its efficacy in ANCA-associated glomerulonephritis is unknown. We induced anti-MPO IgGmediated NCGN by transplanting wild-type bone marrow (BM) into irradiated MPO-deficient mice immunized with MPO. Four weeks after BM transplantation, we treated mice with steroid/cyclophosphamide (S/CYC) or BTZ. Compared with untreated control mice, both S/CYC and BTZ significantly reduced urine abnormalities, NCGN, and infiltration of neutrophils and macrophages. Response to BTZ depended on timing of administration: BTZ abrogated NCGN if begun 3 weeks, but not 5 weeks, after BM transplantation. BTZ treatment significantly reduced total and MPO-specific plasma cells in both the spleen and bone marrow, resulting in significantly reduced anti-MPO titers. Furthermore, BTZ affected neither B cells nor total CD4 and CD8 T cells, including their naive and effector subsets. In contrast, S/CYC reduced the total number of cells in the spleen, including total and MPO-specific plasma cells and B cells. In contrast to BTZ, S/CYC did not affect total and MPO-specific plasma cells in the bone marrow. Three of 23 BTZ-treated mice died within 36 hours after BTZ administration. In summary, BTZ depletes MPO-specific plasma cells, reduces anti-MPO titers, and prevents NCGN in mice.

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“…Among all immune cells studied, pDCs were found to be the most susceptible to the killing effects of bortezomib at physiologically relevant concentrations [37–39]. Other reported negative effects of bortezomib on pDC function include induction of apoptosis through the inhibition of XBP1, which is essential for development of pDCs and other plasma cells [12,37,40–41]. The trafficking of TLR9 from the ER to the endolysosomes and cytokine production in DCs has also been shown to be suppressed by bortezomib [37].…”

Section: Host Responsiveness To Bortezomib Treatmentmentioning

confidence: 99%

Modulatory Effects of Bortezomib on Host Immune Cell Functions

et al. 2015

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Bortezomib is an inhibitor of the ubiquitin-proteasome proteolytic pathway responsible for intracellular protein turnover. Cellular proteins controlled by this pathway represent a diverse group of potential therapeutic targets, particularly in cancer cells, which exploit this proteasomal pathway to promote their growth and diminish apoptosis. Along with inhibiting the proteasome and thus sensitizing tumor cells to apoptosis, bortezomib may also have multiple effects on the host immune responses. This review summarizes the effects that bortezomib may play on immune cell subsets in various disease states in modifying lymphocyte receptors, ligands, the expression of various cytokines and chemokines and their downstream signaling. We also propose steps that can be taken to refine combinatorial strategies that include bortezomib to improve current immunotherapeutic approaches.

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Inhibition of the proteasome influences murine and human dendritic cell development in vitro and in vivo

Cited by 20 publications

References 34 publications

Neddylation plays an important role in the regulation of murine and human dendritic cell function

Neddylation plays an important role in the regulation of murine and human dendritic cell function

Myeloperoxidase-Specific Plasma Cell Depletion by Bortezomib Protects from Anti-Neutrophil Cytoplasmic Autoantibodies–Induced Glomerulonephritis

Modulatory Effects of Bortezomib on Host Immune Cell Functions

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