Interferon-α protects myeloma cell lines from dexamethasone-induced apoptosis

Liu, P; Oken, Martin M.; Ness, Brian Van

doi:10.1038/sj.leu.2401334

Cited by 32 publications

(15 citation statements)

References 23 publications

(39 reference statements)

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“…(34)(35)(36)(37) In a previous work we described that rat placental culture supernatants induced asymmetric IgG glycosylation of anti-DNP IgG1 monoclonal antibodies synthesized by hybridoma cells, which was correlated with a placental supernatant cytotoxic effect on the cells. (24) In addition we have recently reported that heat shock induction in these cells correlated with asymmetric IgG antibody synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the action of dexamethasone on apoptosis, cell proliferation, as well as on antibody synthesis by myeloma cell lines can be reverted by adding IL-6 to the cells. (35,37,40) To assess such hypothesis, we first evaluated the 112D5 ability to synthesize IL-6, and after that, whether it could be modulated by the corticoid. Interleukin-6 was detected in supernatants of hybridoma cell lysates, but no effect of dexamethasone was observed on IL-6 concentration assessed in the cell lysates by ELISA.…”

Section: Discussionmentioning

confidence: 99%

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The Immunomodulatory Action of Dexamethasone on Monoclonal Antibody-Producing Hybridoma Cells

Canellada

Margni²

2002

Hybridoma and Hybridomics

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As found in different studies, glucocorticoid hormones (GCs) as well as interleukin-6 (IL-6) are involved in the modulation of protein glycosylation. In this work we have investigated the immunomodulatory effect of dexamethasone by assessing in vitro IgG glycosylation by monoclonal antibody-producing hybridoma cells. As described in myeloma cell lines, cellular viability and proliferation rates of hybridoma 112D5 cells decrease when cultured with dexamethasone during 24 hours, in a dose-dependent way. Moreover, the corticosteroid triggered apoptosis of the hybridoma, which was observed as soon as 4 h after culturing cells in the presence of the drug. In line with these results, after 24 h, dexamethasone induced a drop in the anti-DNP level of antibodies synthesized by hybridoma 112D5. In previous works we described that asymmetric glycosylation of in vitro synthesized IgG correlated with induction of cell damage. Nevertheless, an increase in asymmetric IgG glycosylation was not observed here, but there was a decrease in the proportion of asymmetrically glycosylated IgG synthesized by the hybridoma after a 4-h culture with the drug. Finally, as results from assessing IL-6 production by ELISA, we conclude that the above described effects of dexamethasone on hybridoma 112D5 cells could not be due to the inhibition of IL-6 synthesis exerted by the corticoid but rather to a direct effect of the drug. Monoclonal antibody (MAb) producing hybridomas provide an excellent in vitro model for the study of the molecular mechanisms involved in immunoglobulin glycosylation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Immunomodulatory Action of Dexamethasone on Monoclonal Antibody-Producing Hybridoma Cells

Canellada

Margni²

2002

Hybridoma and Hybridomics

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“…The suppression of apoptosis was found to be concurrent with the induction of both AP-1 and STAT binding activity. 30 In any case, the results obtained by in vivo studies appear to be more homogeneous in reference to the effectiveness of IFN in the treatment of patients with multiple myeloma. Clinical trials performed to evaluate the efficacy of IFN in the treatment of human multiple myeloma have demonstrated that the treatment of previously untreated patients with IFN is not useful because the response rate is lower than that obtained with chemotherapy.…”

Section: Immunotherapy Of Multiple Myelomamentioning

confidence: 94%

A review of the cytokine network in multiple myeloma

Lauta

2003

Cancer

195

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Because many studies have focused on growth factors in multiple myeloma, the study of the cytokine network appears to be useful for this purpose. Interleukin-6 (IL-6) and IL-2 with their soluble receptors (IL-3, IL-4, IL-10, and IL-11) have been examined. Plasma cells may produce IL-6 by an autocrine mechanism whereas a paracrine mechanism is believed to be involved in the production of IL-6 by bone However, the concomitant evaluation of all immunologic parameters could be more useful than the value of a single IL. Serum levels of IL-6, sIL-6R, sIL-2R, and the expression of membrane-bound IL-2 receptors, both on bone marrow plasma cells and on peripheral blood mononuclear cells, are correlated with disease activity and disease stage. In addition, IL-6 and sIL-6R serum levels are believed to be correlated with the duration of disease-free survival because a high serum level at the time of diagnosis is believed to be correlated with a short duration of survival. However, some laboratory parameters may express the same prognostic value as high ␤ 2 microglobulin and lactate dehydrogenase (LDH) serum levels together with a high plasma cell labeling index are correlated with disease activity.Furthermore, if the evaluation is performed at the time of diagnosis, high values of these parameters are correlated with a short disease-free survival. A correlation between laboratory parameters and the serum level of several cytokines was demonstrated. Hence, the real advantage of the prognostic evaluation of cytokines is reserved for patients who do not exhibit uniform results with regard to ␤ 2 microglobulin and LDH serum levels, or, better, for borderline cases. With regard to the differential diagnosis, all immunologic parameters should be evaluated concomitantly rather than separately to confer a real prognostic value to results. Furthermore, a particular relation was found between a high sIL-6R serum level and a poor response to chemotherapy, therefore suggesting the possibility of identifying in advance a subset of patients with a high risk of treatment failure, as has already been demonstrated in other hematologic malignancies.Finally, the majority of studies indicate that interferons are used mainly in the immunotherapy for multiple myeloma, whereas many clinical trials should still be required for the evaluation of the effectiveness of anti-I-L6 antibodies or antiidiotypic vaccines in reference to the eligible patients for these particular therapies.

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“…However, an antagonizing effect for IFNs on TRAILinduced caspase-8 activation has been identified (10). In several studies, IFN-α protected myeloma cells from dexamethasoneinduced apoptosis (7,14), suggesting antiapoptotic activity for IFNs in myeloma. However, molecular mechanisms for antiapoptotic effects of IFNs in malignancies have remained unclear.…”

Section: Introductionmentioning

confidence: 99%

G1P3, an IFN-induced survival factor, antagonizes TRAIL-induced apoptosis in human myeloma cells

et al. 2007

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The effectiveness of IFN-α2b for human multiple myeloma has been variable. TRAIL has been proposed to mediate IFN-α2b apoptosis in myeloma. In this study we assessed the effects of IFN-α2b signaling on the apoptotic activity of TRAIL and human myeloma cell survival. While TRAIL was one of the most potently induced proapoptotic genes in myeloma cells following IFN-α2b treatment, less than 20% of myeloma cells underwent apoptosis. Thus, we hypothesized that an IFN-stimulated gene (ISG) with prosurvival activity might suppress TRAIL-mediated apoptosis. Consistent with this, IFN-α2b stabilized mitochondria and inhibited caspase-3 activation, which antagonized TRAIL-mediated apoptosis and cytotoxicity after 24 hours of cotreatment in cell lines and in fresh myeloma cells, an effect not evident after 72 hours. Induced expression of G1P3, an ISG with largely unknown function, was correlated with the antiapoptotic activity of IFN-α2b. Ectopically expressed G1P3 localized to mitochondria and antagonized TRAIL-mediated mitochondrial potential loss, cytochrome c release, and apoptosis, suggesting specificity of G1P3 for the intrinsic apoptosis pathway. Furthermore, RNAimediated downregulation of G1P3 restored IFN-α2b-induced apoptosis. Our data identify the direct role of a mitochondria-localized prosurvival ISG in antagonizing the effect of TRAIL. Curtailing G1P3-mediated antiapoptotic signals could improve therapies for myeloma or other malignancies.

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Interferon-α protects myeloma cell lines from dexamethasone-induced apoptosis

Cited by 32 publications

References 23 publications

The Immunomodulatory Action of Dexamethasone on Monoclonal Antibody-Producing Hybridoma Cells

The Immunomodulatory Action of Dexamethasone on Monoclonal Antibody-Producing Hybridoma Cells

A review of the cytokine network in multiple myeloma

G1P3, an IFN-induced survival factor, antagonizes TRAIL-induced apoptosis in human myeloma cells

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