The proteasome inhibitor bortezomib disrupts tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and natural killer (NK) cell killing of TRAIL receptor-positive multiple myeloma cells

2010 ◽  
Vol 47 (14) ◽  
pp. 2388-2396 ◽  
Author(s):  
Xiaoli Feng ◽  
Jie Yan ◽  
Yibiao Wang ◽  
Juleen R. Zierath ◽  
Magnus Nordenskjöld ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Necrosis Factor ◽  
Natural Killer ◽  
Proteasome Inhibitor ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Trail Receptor ◽  
Trail Expression ◽  
Myeloma Cells ◽  
Necrosis Factor

Proteasome Inhibitor Bortezomib Disrupts Tumor Necrosis Factor-Related Apoptosis-Inducing ligand (TRAIL) Expression and Natural Killer (NK) Cell Killing of TRAIL Receptor-Positive Multiple Myeloma Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5021-5021
Author(s):  
Xiaoli Feng ◽  
Jie Yan ◽  
Yibiao Wang ◽  
Juleen R. Zierath ◽  
Magnus Nordenskjöld ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Proteasome Inhibitor ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Dependent Manner ◽  
Trail Expression ◽  
Myeloma Cells ◽  
Dose Dependent ◽  
Necrosis Factor

Abstract Abstract 5021 Bortezomib, a potent 26S proteasome inhibitor, is approved for the treatment of multiple myeloma (MM) and clinical trials are under way to evaluate its efficacy in other malignant diseases. However, cytotoxic effects of bortezomib on immune-competent cells have also been observed. The aim of this study was to investigate the putative effects of Bortezomib on activated human natural killer (NK) cell function. In this project, primary lymphocytes or NK cells were isolated or purified from peripheral blood mononuclear cells of healthy donors. Expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by interleukin (IL)-2-activated NK cells was quantified by flow cytometry and real time-PCR method. NK cell degranulation activity and cytotoxicity against MM cell lines were evaluated by CD107a surface translocation and 51Cr release assays, respectively. Our results demonstrate that bortezomib markedly downregulated cell surface expression of TRAIL on primary human IL-2-activated NK cells in a dose-dependent manner. Moreover, bortezomib reduced TRAIL mRNA expression in these cells, suggesting that bortezomib regulates TRAIL expression of activated NK cells at the transcriptional level. Interestingly, pharmacological inhibition of the transcription factor NF-κB also profoundly decreased TRAIL expression both at protein and mRNA levels, indicating a novel role of NF-κB in the regulation of TRAIL expression in activated human NK cells. Furthermore, perforin-independent killing of the human MM cell lines was significantly suppressed following bortezomib treatment. In addition, blocking cell surface-bound TRAIL with a TRAIL antibody impaired lymphokine-activated killer (LAK) cell-mediated lysis of the TRAIL-sensitive MM cell line, RPMI8226. Our study demonstrated that bortezomib decreases TRAIL expression by IL-2 activated NK cells in a dose-dependent manner and disrupts TRAIL-mediated killing of TRAIL-sensitive myeloma cells, suggesting that Bortezomib may potentially hamper NK-dependent immunosurveillance against tumors in patients treated with this drug. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (Trail) Contributes to Interferon γ–Dependent Natural Killer Cell Protection from Tumor Metastasis

2001 ◽  
Vol 193 (6) ◽  
pp. 661-670 ◽  
Author(s):  
Mark J. Smyth ◽  
Erika Cretney ◽  
Kazuyoshi Takeda ◽  
Robert H. Wiltrout ◽  
Lisa M. Sedger ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Critical Role ◽  
Trail Expression ◽  
Ifn Γ ◽  
Necrosis Factor

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is expressed by in vitro activated natural killer (NK) cells, but the relevance of this observation to the biological function of NK cells has been unclear. Herein, we have demonstrated the in vivo induction of mouse TRAIL expression on various tissue NK cells and correlated NK cell activation with TRAIL-mediated antimetastatic function in vivo. Expression of TRAIL was only constitutive on a subset of liver NK cells, and innate NK cell control of Renca carcinoma hepatic metastases in the liver was partially TRAIL dependent. Administration of therapeutic doses of interleukin (IL)-12, a powerful inducer of interferon (IFN)-γ production by NK cells and NKT cells, upregulated TRAIL expression on liver, spleen, and lung NK cells, and IL-12 suppressed metastases in both liver and lung in a TRAIL-dependent fashion. By contrast, α-galactosylceramide (α-GalCer), a powerful inducer of NKT cell IFN-γ and IL-4 secretion, suppressed both liver and lung metastases but only stimulated NK cell TRAIL-mediated function in the liver. TRAIL expression was not detected on NK cells from IFN-γ–deficient mice and TRAIL-mediated antimetastatic effects of IL-12 and α-GalCer were strictly IFN-γ dependent. These results indicated that TRAIL induction on NK cells plays a critical role in IFN-γ–mediated antimetastatic effects of IL-12 and α-GalCer.

scholarly journals An Essential Role for Tumor Necrosis Factor in Natural Killer Cell–mediated Tumor Rejection in the Peritoneum

1998 ◽  
Vol 188 (9) ◽  
pp. 1611-1619 ◽  
Author(s):  
Mark J. Smyth ◽  
Janice M. Kelly ◽  
Alan G. Baxter ◽  
Heinrich Körner ◽  
Jonathon D. Sedgwick
Keyword(s):  
Tumor Necrosis Factor ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Tumor Rejection ◽  
Class I ◽  
Deficient Mice ◽  
Necrosis Factor

Natural killer (NK) cells are thought to provide the first line of defence against tumors, particularly major histocompatibility complex (MHC) class I− variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I− RMA-S tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3− NK1.1+ cells. Furthermore, we demonstrate that B6 mice lacking tumor necrosis factor (TNF) are also significantly defective in their rejection of RMA-S, despite the fact that RMA-S is insensitive to TNF in vitro and that spleen NK cells from B6 and TNF-deficient mice are equally lytic towards RMA-S. NK cell recruitment into the peritoneum was abrogated in TNF-deficient mice challenged with RMA-S or RM-1, a B6 MHC class I− prostate carcinoma, compared with B6 or perforin-deficient mice. The reduced NK cell migration to the peritoneum of TNF-deficient mice correlated with the defective NK cell response to tumor in these mice. By contrast, a lack of TNF did not affect peptide-specific cytotoxic T lymphocyte–mediated rejection of tumor from the peritoneum of preimmunized mice. Overall, these data show that NK cells delivering perforin are the major effectors of class I− tumor rejection in the peritoneum, and that TNF is specifically critical for their recruitment to the peritoneum.

The Induction of Nitric Oxide by Interleukin-12 and Tumor Necrosis Factor- in Human Natural Killer Cells: Relationship With the Regulation of Lytic Activity

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 2093-2102 ◽  
Author(s):  
Ombretta Salvucci ◽  
Jean Pierre Kolb ◽  
Bernard Dugas ◽  
Nathalie Dugas ◽  
Salem Chouaib
Keyword(s):  
Nitric Oxide ◽  
Tumor Necrosis Factor ◽  
Cytotoxic Activity ◽  
Natural Killer ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Lytic Activity ◽  
Interleukin 12 ◽  
Target Cells ◽  
Necrosis Factor

Abstract We have investigated the interleukin-12 (IL-12) and tumor necrosis factor- (TNF)-induced regulation of human natural killer (NK) cell function and their relationship with nitric oxide (NO) generation. We demonstrate that both cytokines were efficient to trigger the transcription of the inducible nitric oxide synthase (iNOS) mRNA, as detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Western blot analysis and intracytoplasmic fluorescence showed that iNOS protein was also induced by both cytokines. However, our data indicate that NO does not play a significant role in the effector phase of the cytotoxic activity mediated by NK-stimulated cells, inasmuch as the lytic activity was not affected in the presence of specific NO synthase inhibitors. When aminoguanidine (AMG), an inhibitor of iNOS, was added during the afferent phase of NK stimulation with IL-12 and TNF, a subsequent increase in the lytic potential of the effector cells towards the NK-sensitive target cells (K562) and lymphokine-activated killer (LAK) target cells (Daudi) was observed. Conversely, the addition of chemical NO donors during the afferent step resulted in a dose-dependent inhibition of the NK and LAK cytotoxicity. Our data suggest that the enhancement of NK-cell cytotoxic activity resulting from iNOS inhibition may be correlated, at least in part, to an increase in interferon-γ production and granzyme B expression. © 1998 by The American Society of Hematology.

The Induction of Nitric Oxide by Interleukin-12 and Tumor Necrosis Factor- in Human Natural Killer Cells: Relationship With the Regulation of Lytic Activity

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 2093-2102 ◽  
Author(s):  
Ombretta Salvucci ◽  
Jean Pierre Kolb ◽  
Bernard Dugas ◽  
Nathalie Dugas ◽  
Salem Chouaib
Keyword(s):  
Nitric Oxide ◽  
Tumor Necrosis Factor ◽  
Cytotoxic Activity ◽  
Natural Killer ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Lytic Activity ◽  
Interleukin 12 ◽  
Target Cells ◽  
Necrosis Factor

We have investigated the interleukin-12 (IL-12) and tumor necrosis factor- (TNF)-induced regulation of human natural killer (NK) cell function and their relationship with nitric oxide (NO) generation. We demonstrate that both cytokines were efficient to trigger the transcription of the inducible nitric oxide synthase (iNOS) mRNA, as detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Western blot analysis and intracytoplasmic fluorescence showed that iNOS protein was also induced by both cytokines. However, our data indicate that NO does not play a significant role in the effector phase of the cytotoxic activity mediated by NK-stimulated cells, inasmuch as the lytic activity was not affected in the presence of specific NO synthase inhibitors. When aminoguanidine (AMG), an inhibitor of iNOS, was added during the afferent phase of NK stimulation with IL-12 and TNF, a subsequent increase in the lytic potential of the effector cells towards the NK-sensitive target cells (K562) and lymphokine-activated killer (LAK) target cells (Daudi) was observed. Conversely, the addition of chemical NO donors during the afferent step resulted in a dose-dependent inhibition of the NK and LAK cytotoxicity. Our data suggest that the enhancement of NK-cell cytotoxic activity resulting from iNOS inhibition may be correlated, at least in part, to an increase in interferon-γ production and granzyme B expression. © 1998 by The American Society of Hematology.

scholarly journals Decrease of natural killer cell activity and monokine production in peripheral blood of patients treated with recombinant tumor necrosis factor

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 344-348 ◽  
Author(s):  
A Kist ◽  
AD Ho ◽  
U Rath ◽  
B Wiedenmann ◽  
A Bauer ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Natural Killer ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Cell Activity ◽  
Mononuclear Leukocytes ◽  
Nk Cell Activity ◽  
Necrosis Factor

Abstract Tumor necrosis factor (TNF), a protein predominantly produced by activated macrophages/monocytes, is presently available in recombinant, purified form for clinical trials. Intensive studies in many laboratories have shown that besides the tumorcytotoxic effects, TNF acts on a large array of different cells and has potent immunomodulatory activities. In a clinical phase I study, some immunologic functional parameters of blood cells from patients who received 24-hour infusions of recombinant human TNF (rhTNF) were analyzed. Natural killer (NK) cell activity, TNF production, interleukin-1 (IL-1) production and mitogen-induced proliferation were measured either in whole blood samples or in cultures of peripheral mononuclear leukocytes of the patients directly before and after rhTNF infusion. NK cell activity, TNF and IL-1 production capacity and proliferative responses to concanavalin A (Con A) were significantly reduced after rhTNF application. We conclude from these observations that rhTNF in vivo acts directly or indirectly on NK cells and monocytes by either inactivating their functional capacity or by absorbing the relevant cells to the endothelial cell layer, thus removing them from circulation.

scholarly journals Natural killer (NK) cell-derived hematopoietic colony-inhibiting activity and NK cytotoxic factor. Relationship with tumor necrosis factor and synergism with immune interferon.

1985 ◽  
Vol 162 (5) ◽  
pp. 1512-1530 ◽  
Author(s):  
G Degliantoni ◽  
M Murphy ◽  
M Kobayashi ◽  
M K Francis ◽  
B Perussia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Necrosis Factor ◽  
Natural Killer ◽  
Cell Lines ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Inhibiting Activity ◽  
Ifn Gamma ◽  
Cytotoxic Factor ◽  
Necrosis Factor

We characterize the natural killer (NK) cell colony-inhibiting activity (CIA) produced in supernatants from cultures of human peripheral blood lymphocytes (PBL) with NK-sensitive target cell lines, and study its relationship with NK cell-derived cytotoxic factor (NKCF). Using monoclonal antibodies (mAb) specific for NK cells or other lymphocyte populations, we unambiguously identify NK cells as the only PBL subset able to produce both NKCF and NK-CIA. We present functional and biochemical data suggesting that NKCF and NK-CIA represent the same molecule: (a) a highly significant positive correlation exists between the quantity of NKCF and NK-CIA in supernatants independently produced by different PBL subsets; (b) both NK-CIA and NKCF are induced by culture of PBL with NK-sensitive, but not with NK-insensitive cell lines, and with HLA-DR+ bone marrow cells; (c) both NKCF and NK-CIA are absorbed on the same cell lines or bone marrow cell types; (d) the two activities coelute in the same gel filtration fractions; (e) D-mannose-6-phosphate blocks both NKCF and NK-CIA activity, and prevents their absorption by K562 cells; and (f) both NKCF and NK-CIA activity are lost after 2 d at 37 degrees C. The NK-CIA-containing preparations are devoid of antiviral activity, and antiinterferon (anti-IFN) antibodies do not block the inhibitor activity of NK-CIA. The effect of NK-CIA on day 14 (early) colony-forming units of granulocytes and macrophages (CFU-GM) is synergistic with that of IFN-gamma, and this synergy is also evident on day 7 (late) CFU-GM growth. A combination of NK-CIA and IFN-gamma suppresses late CFU-GM, at concentrations of the two lymphokines that are completely ineffective when used independently. No synergy between NK-CIA and IFN-alpha or -beta was observed, due to a direct inhibitory effect of these two IFN types on late CFU-GM. Antibodies specific for tumor necrosis factor (TNF), but not those specific for lymphotoxins, inhibit both NK-CIA and NKCF activity in the NK cell-derived supernatant. Recombinant TNF, in the range of concentrations corresponding to that of the cytotoxic activity on L-929 cells present in supernatants, mediated both NKCF and NK-CIA activity.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Decrease of natural killer cell activity and monokine production in peripheral blood of patients treated with recombinant tumor necrosis factor

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 344-348
Author(s):  
A Kist ◽  
AD Ho ◽  
U Rath ◽  
B Wiedenmann ◽  
A Bauer ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Natural Killer ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Cell Activity ◽  
Mononuclear Leukocytes ◽  
Nk Cell Activity ◽  
Necrosis Factor

Tumor necrosis factor (TNF), a protein predominantly produced by activated macrophages/monocytes, is presently available in recombinant, purified form for clinical trials. Intensive studies in many laboratories have shown that besides the tumorcytotoxic effects, TNF acts on a large array of different cells and has potent immunomodulatory activities. In a clinical phase I study, some immunologic functional parameters of blood cells from patients who received 24-hour infusions of recombinant human TNF (rhTNF) were analyzed. Natural killer (NK) cell activity, TNF production, interleukin-1 (IL-1) production and mitogen-induced proliferation were measured either in whole blood samples or in cultures of peripheral mononuclear leukocytes of the patients directly before and after rhTNF infusion. NK cell activity, TNF and IL-1 production capacity and proliferative responses to concanavalin A (Con A) were significantly reduced after rhTNF application. We conclude from these observations that rhTNF in vivo acts directly or indirectly on NK cells and monocytes by either inactivating their functional capacity or by absorbing the relevant cells to the endothelial cell layer, thus removing them from circulation.

Sign in / Sign up

Export Citation Format

Share Document