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Is a Survival Factor for Human Myeloma Cells and Reduces Dexamethasone-Induced Apoptosis1
*
Institut National de la Santé et de la Recherche Médicale, Unit 475,
Service des Maladies du Sang B, Centre Hospitalier Universitaire Montpellier, and
Unit for Cellular Therapy, Centre Hospitalier Universitaire Montpellier, Hôpital Saint Eloi, Montpellier, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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is used as a maintenance therapy in patients with multiple
myeloma, but its benefit is a matter of controversy. In vitro studies
show that IFN- can both stimulate and inhibit myeloma cell
proliferation. We have tested the effect of IFN- on the survival of
myeloma cell lines and primary plasma cells. IFN- significantly
reduced the apoptosis induced by removal of IL-6 in four IL-6-dependent
myeloma cell lines. It also reduced the level of apoptosis induced by
dexamethasone in these cell lines as well as in purified primary
myeloma cells from seven patients. IFN- promoted the survival of
myeloma cells, which, following removal of IL-6, were blocked in G1 and
died. However, unlike IL-6, IFN--treated cells remained mainly
blocked in the G1 phase of the cycle. While the effects of IL-6 are
mediated through stimulation of its gp130 receptor subunit, the
IFN--induced survival of myeloma cells was independent of gp130
transducer activation (as demonstrated using a neutralizing
anti-gp130 Ab). However, the signal transduction cascades activated
by these two cytokines share at least some common elements, since
stimulation with either IFN- or IL-6 resulted in STAT3
phosphorylation. These results indicate that IFN- promotes the
survival, but not the proliferation, of myeloma cells, preventing the
apoptosis induced by removal of IL-6 or addition of dexamethasone. This
survival factor activity may explain the conflicting reports on the
effects of IFN- on myeloma cell
proliferation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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as a maintenance therapy in patients with multiple
myeloma (MM)3 is a matter of
debate. As recently reviewed by the European Myeloma Research group
(1), this cytokine had a beneficial effect in three randomized studies,
whereas in three other protocols, it had no effect. Preliminary reports
suggested that IFN- could be of benefit as a maintenance treatment
following high dose chemotherapy or in combination with corticosteroids
(2, 3). The controversy concerning the in vivo use of IFN- is
further emphasized by in vitro studies showing that under various
conditions IFN- can either stimulate or inhibit myeloma cell
proliferation (4, 5, 6, 7, 8). IL-6 and more generally the cytokines, which
activate the gp130 receptor subunit, are the main survival and growth
factors of malignant plasma cells (9). In particular, myeloma cell
lines whose survival and growth are dependent upon addition of
exogenous IL-6 can be reproducibly obtained from patients with terminal
disease (10, 11). As IFN- shares some common transduction pathways
with IL-6 (12, 13, 14, 15), we compared its effect on the survival of myeloma
cells with that of IL-6.
Using both IL-6-dependent myeloma cell lines (11) and primary myeloma
cells, we demonstrate that IFN- is a survival factor for malignant
plasma cells. IFN- reduced the apoptosis induced by removal of IL-6
in all four myeloma cell lines studied. It also inhibited dexamethasone
(DEX)-induced apoptosis of the myeloma cell lines and of primary
myeloma cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tumor samples were obtained from seven patients (no. 1–7) with MM (median age, 57 yr) after written informed consent was received. According to the Durie-Salmon classification, three patients were stage IIIB, and four were stage IIIA. Two patients had IgGl MM, one had IgGk MM, three had Bence-Jones l MM, and one had Bence-Jones k MM.
Reagents
Recombinant IL-6 was provided by Dr. Ytier (Ares Serono, Geneva,
Switzerland). Recombinant IFN-2b was provided by Shering-Plough
(Levallois-Perret, France). DEX was purchased from Sigma (St. Louis,
MO) and was dissolved in ethanol at a concentration of
10-2 M, filtered, and further diluted in RPMI 1640. The
neutralizing (A1) and nonneutralizing (G4) mAbs to gp130 have been
previously described (16). A1 has been shown to neutralize the activity
of IL-6, leukemia inhibitory factor, oncostatin M, and ciliary
neurotropic factor (16). An anti-IFN--neutralizing sheep
polyclonal Ab was the gift of Dr. G. Uze (Centre National de la
Recherche Scientifique, Montpellier, France). Rabbit phospho-specific
STAT1 and STAT3 Abs were purchased from New England Biolabs (Beverly,
MA), mouse anti-STAT1 and STAT3 were obtained from Transduction
Laboratories (Lexington, KY), Abs to Bcl-2 (124) were purchased from
Dako (Carpinteria, CA), anti-Bcl-XL (S-18) and
anti-Bax (SC-493) were obtained from Santa Cruz Biotechnology
(Santa Cruz, CA), peroxidase-conjugated goat anti-mouse Abs were
purchased from Bio-Rad (Hercules, CA), and peroxidase-conjugated goat
anti-rabbit Abs and control purified murine IgG1 were obtained from
Sigma.
Isolation of primary myeloma cells
Patients’ myeloma cells were purified using the anti-myeloma cell MI15 mAb and Dynal magnetic beads (Dynal M450, Dynal, Oslo, Norway) coated with sheep anti-mouse IgG as previously described in detail (17). The MI15 mAb recognizes syndecan-1, which is present only on myeloma cells (18, 19). This procedure yielded cell populations comprised of >95% viable myeloma cells. Purified myeloma cells were resuspended in RPMI 1640 medium supplemented with 10% FCS.
Human myeloma cell lines (HMCL)
Four HMCL were studied : XG-1, XG-2, XG-4, and XG-6. All had cytoplasmic Ig, expressed plasma cell Ags (CD38 and syndecan-1), and lacked the usual B cell Ags (CD19 and CD20). Their growth was completely dependent on addition of exogenous IL-6. Detailed characteristics of these lines have been reported previously (11). U266 and RPMI 8226 HMCL were purchased from American Type Culture Collection (Manassas, VA).
Cell culture
Cells were grown in RPMI 1640 medium with 10% FCS and/or
cytokines. To investigate the effects of cytokines (IFN-, IL-6) and
DEX on apoptosis, cells were washed once with culture medium, incubated
for 5 h at 37°C in culture medium alone, and then washed twice
to remove rIL-6. They were then cultured at a cell concentration of
3 x 105 cells/ml either without exogenous cytokine or
with IFN- (100 U/ml), IL-6 (3 ng/ml), or IFN- (100 U/ml) and IL-6
(3 ng/ml). The same culture conditions were used in the presence or the
absence of DEX (10-7 M). In some culture groups, cells
were cultured with 150 µg of an anti-gp130-neutralizing (A1) or
nonneutralizing (G4) IgG1 mAb or control murine IgG1.
Proliferation and growth assay of myeloma cell lines
To investigate the effects of IFN- and/or IL-6 in the
presence or the absence of neutralizing or nonneutralizing
anti-gp130 transducer mAb on the proliferation of HMCL, cells were
washed to remove bound rIL-6. They were cultured for 5 h with
culture medium, washed again, and incubated in 96-well flat-bottom
microplates for 5 days with either culture medium alone or the
different cytokines and/or mAbs. Tritiated thymidine (0.5 µCi/mM;
CEA, Saclay, France) was added for the last 8 h of culture, and
incorporation was determined on a beta scintillation counter.
Assays for detection of apoptotic cells
Apoptosis was assessed by propidium iodide (PI) or annexin V staining. To detect apoptotic cells by PI staining, cells were washed twice with PBS, resuspended in 70% ethanol, and incubated at 4°C overnight. After two washes with PBS, cells were resuspended in 940 µl of PBS, 10 µl of RNase A (10 mg/ml; Boehringer Mannheim, Meylan, France), and 50 µl of PI (1 mg/ml; Sigma) and incubated in the dark at room temperature for 30 min at 37°C before flow cytometric analysis on a FACScan apparatus (Becton Dickinson, San Jose, CA). Apoptotic cells were also detected using annexin V-fluos (Boehringer Mannheim), which has a high affinity for phosphatidylserine present in the outer membrane of apoptotic cells (20). Cells were washed twice in PBS and resuspended in 100 µl of labeling solution containing 2 µl of annexin and 2 µl of PI (50 µg/ml) in HEPES buffer (HEPES/NaOH, pH 7.4; 140 mM NaCl; and 5 mM CaCl2) for 20 min at room temperature. After two washes with HEPES buffer, the fluorescence of FL1-H (annexin V-fluos) and FL2-H (PI) was analyzed on a FACScan flow cytometer (Becton Dickinson).
Cell stimulation and Western blot analysis
To assay for IFN-- or IL-6-mediated signal transduction in
myeloma cells, XG cells were washed twice and cultured (2 x
106 cells/ml) without IL-6 for 12 h in RPMI 1640 and
1% FCS at 37°C. Cells were then stimulated with IFN- (500 U/ml)
or IL-6 (25 ng/ml) for 15 min at 37°C and immediately lysed at 4°C
in 10 mM Tris-HCl (pH 7.05), 50 mM NaCl, 50 mM NaF, 30 mM sodium
pyrophosphate, 1% Triton X-100, 5 mM ZnCl2, 100 mM
Na3VO4, 1 mM DTT, 20 mM ß-glycerophosphate,
20 mM p-nitrophenolphosphate, 2.5 mg/ml aprotinin, 2.5 mg/ml
leupeptin, 0.5 mM PMSF, 0.5 mM benzamidine, 5 mg/ml pepstatin, and 50
nM okadaic acid. After centrifugation at 14,000 x g,
the supernatant was resolved on a 10% SDS-PAGE gel and transferred to
a nitrocellulose membrane (Schleicher and Schuell, Dassel, Germany).
Membranes were blocked for 1 h at room temperature in 138 mM NaCl,
3 mM KCl, 25 mM Tris-HCl (pH 7.4), and 0.1% Tween-20 (TBS-T)
containing 5% BSA. They were then incubated for 1 h at room
temperature with primary Ab (phospho-specific STAT1 or STAT3 at a
1/1000 dilution), and the primary Abs were visualized with a
peroxidase-conjugated goat anti-rabbit Ab (Sigma) and enhanced
chemiluminescence (Amersham Life Science, Arlington Heights, IL). The
membranes were stripped by two 30-min incubations in a solution
containing 100 mM glycine (pH 2.2), 0.1% Nonidet P-40, and 1% SDS.
They were reprobed with anti-STAT1 or anti-STAT3 Abs (at a
1/2000 dilution in 1% BSA TBS-T), and the Abs were visualized with
peroxidase-conjugated goat anti-mouse Abs followed by enhanced
chemiluminescence. In separate experiments, other membranes were probed
with Abs to Bcl-2, Bcl-XL, Bax, or
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) that were all used at
a 1/1000 dilution in 20 mM Tris-HCl (pH 7.4), 150 mM NaCl, and 0.1%
Tween-20/5% milk. Peroxidase-conjugated secondary Abs were then used
at a 1/1000 dilution, and reactivity was revealed by enhanced
chemiluminescence and was quantified using the Intelligent Quantifier
(Bio Image, Ann Arbor, MI).
Statistical analysis
For a given cell line, each experiment was repeated five times to compare apoptosis in different culture groups, and significance was assessed by paired t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is a survival factor for cytokine-dependent myeloma cell
lines
To investigate the effect of IFN- on myeloma cell survival, we
used cell lines whose survival and proliferation are dependent on
addition of exogenous IL-6. As cells necrotized by day 4 after IL-6
removal, apoptosis was studied on day 3 in the following experiments.
Apoptosis was evaluated by PI staining of DNA content and additionally
by combined annexin V and PI staining (see Materials and
Methods). The two methodologies yielded similar results, although
apoptotic cells were detected earlier with annexin V, as illustrated in
Figure 1
for XG-4 HMCL. Upon removal of
IL-6, approximately 50% of the myeloma cells died by apoptosis within
3 days, and IFN- significantly reduced the percentage of apoptosis
in five separate experiments (Fig. 1 and Table I). This effect was specific to IFN-,
as it was inhibited by neutralizing Abs to IFN- (Fig. 2). Similar results were found for all
four IL-6 dependent cell lines in five separate experiments as
illustrated in Figure 3. The survival
effect of IFN- was maximal at a concentration of 100 U/ml and did
not change with 1,000 or 10,000 U/ml. Results for the XG-1 HMCL are
shown in Figure 4. IL-6 induced maximal
survival at a concentration of 1 ng/ml. For the same XG HMCL, the
survival activity of IFN- was generally weaker than that of IL-6
(Table I and Fig. 3), but in some experiments, IFN- was as potent as
IL-6 (Table I and Fig. 4A). In addition, the survival
activities of IFN- and IL-6 were additive when suboptimal
concentrations of IL-6 were used (Fig. 4B).
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reduces DEX-induced apoptosis in myeloma cell lines
The effect of IFN- on myeloma cell survival led us to assess
whether this cytokine could reduce apoptosis induced by DEX. DEX
increased the level of apoptosis in myeloma cells cultured for 24 or
48 h without cytokines (Figs. 5 and
6). Both IL-6 and IFN- significantly
reduced the level of DEX-induced apoptosis, especially for XG-2 and
XG-6 HMCL, but IL-6 was generally more efficient than IFN- (Figs. 5 and 6). Although IFN- induced a survival activity on IL-6-dependent
HMCL, this phenomenon was not observed in autonomously growing HMCL,
such as U266 or RPMI 8226. It was not possible to assess the effect of
IFN- on DEX-induced apoptosis in the IL-6-independent lines, since,
in contrast to a previous report (21), we did not find that DEX induced
apoptosis in either U266 or in RPMI 8226 (results not shown).
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reduces DEX-induced apoptosis in primary myeloma cells
We next investigated the effect of IFN- on the survival and
DEX-induced apoptosis of primary plasma cells purified from seven
myeloma patients. Following purification, 95% of the cell populations
were viable myeloma cells. Detailed results obtained with myeloma cells
from one patient are shown in Figure 7
and summaries of the results with myeloma cells from the seven patients
are presented in Table II. DEX induced a
strong apoptosis in purified primary myeloma cells, while IL-6
significantly inhibited this effect. For six of the seven patients,
IFN- also significantly reduced DEX-induced apoptosis (Fig. 7 and
Table II).
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is a gp130-independent myeloma cell survival factor
In a previous report, we showed that a weak proliferation of the
XG-1 myeloma cell line in the presence of IFN- was due to autocrine
production of IL-6 (6). As IL-6 and other cytokines that activate
signaling cascades through gp130 are the major survival factors for
myeloma cells (9, 22, 23), we investigated whether the
anti-apoptotic effect of IFN- was mediated through the autocrine
production of gp130 cytokine in the XG-1 and XG-6 cell lines. A high
concentration (150 µg/ml) of a neutralizing (A1) anti-gp130 mAb
was used to block gp130 activation, and a nonneutralizing
anti-gp130 mAb (G4) was used as a control. The anti-apoptotic
effect of IL-6 was completely inhibited by the neutralizing A1
anti-gp130 mAb, but was unaffected by the nonneutralizing G4 mAb
(Figs. 8, A and B).
In contrast, the anti-apoptotic effect of IFN- was not affected
by the anti-gp130-neutralizing mAb (Fig. 8, A and
B). These data indicate that the myeloma cell survival
activity of IFN- was independent of gp130 transducer activation. The
neutralizing anti-gp130 mAb inhibited the weak proliferation
obtained in the presence of IFN- by approximately 50%, suggesting
that it was mediated through an autocrine gp130 cytokine (Fig. 8, A and B). To further study the effect of IFN-
on proliferation, we took advantage of a property of the XG-2 HMCL to
accumulate in the G1 phase of the cell cycle upon removal of IL-6 (Fig. 9). In the other myeloma cell lines,
although removal of IL-6 induced apoptosis, only a partial blockage of
the cell cycle was observed (Fig. 1
). IFN- was a survival factor for
XG-2 cells, but unlike IL-6, IFN--treated cells were mainly blocked
in G1 (Fig. 9). This blockage was reversible, since addition of IL-6
together with IFN- resulted in their entry into the cell cycle.
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in these myeloma cells, we assessed whether the
transcriptional activators, STAT1 and STAT3, were stimulated following
treatment with this cytokine. It has been previously shown that
stimulation of gp130 results in phosphorylation and activation of both
STAT1 and STAT3 (24). Additionally, IFN- has been found to activate
STAT1 and STAT3 in myeloma cells (7). After culture under conditions
where cells were deprived of IL-6 for 16 h, addition of IFN-
induced a phosphorylation of the STAT1 and STAT3 activators in the XG-2
HMCL, but only STAT3 activation was detected in the XG-1 HMCL (Fig. 10). IL-6 also induced phosphorylation
of STAT1 and STAT3 in XG-2 HMCL and of STAT3 in XG-1 HMCL (Fig. 10).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is a survival factor
for IL-6-dependent myeloma cell lines that are induced to apoptosis
upon removal of IL-6. IFN- also blocked the apoptosis induced by DEX
in these cell lines and in primary cells from myeloma patients. For the
different cell lines, we found that a maximal survival activity was
obtained with 100 U/ml of IFN- and did not change at concentrations
up to 10,000 U/ml.
It was important to elucidate whether the survival factor activity of
IFN- was dependent upon a low production of IL-6 or another
gp130-activating cytokine. Indeed, IL-6 or the gp130
transducer-activating cytokines are the main survival factors for
myeloma cells (25). In addition, we have previously shown that a weak
proliferation of the XG-1 myeloma cell line in the presence of IFN-
was due to an autocrine production of IL-6 (6). In the presence of a
high concentration of an anti-gp130 mAb that completely inhibited
the biologic activities of IL-6 and other gp130 activating cytokines
(16, 22), IFN--induced survival was not affected. In contrast, this
neutralizing anti-gp130 mAb inhibited the weak proliferation
obtained in the presence of IFN- by approximately 50%. It also
completely inhibited the survival and growth factor activity of IL-6.
These data strongly suggest that the observed IFN--induced survival
is independent of gp130 transducer activation and that IFN- is not a
myeloma cell proliferation factor. This is further supported by data
obtained with the XG-2 HMCL. In the presence of IL-6, XG-2 myeloma
cells survived and highly proliferated. Upon removal of IL-6, XG-2
cells were blocked in the G1 phase and then died. IFN- could promote
the survival of these cells, but they remained mainly blocked in the G1
phase of the cell cycle. These data are in agreement with a recent
report showing that IFN- blocked Fas-induced apoptosis in
autonomously growing lymphoblastoid and myeloma cell lines (26). The
mechanism regulating this process in myeloma cells has not yet been
determined, and we failed to find reproducible changes in the levels of
the Bcl-2 or Bcl-XL antiapoptotic or Bax proapoptotic
proteins following addition of IFN- (results not shown).
We have now identified two cytokines, IFN- and IL-6, that are
myeloma cell survival factors. The transduction pathways induced by
gp130 transducer activation have become better characterized.
Dimerization of gp130 by IL-6 induces phosphorylation of tyrosine
residues on JAK kinases that are preassociated with gp130 (13, 24).
This allows the recruitment of STAT1 and STAT3, and phosphorylation of
STAT results in further activation of genes by STAT homodimers or
heterodimers. Activation of gp130 also stimulates the Ras/MAP kinase
pathway through binding of SHP-2 or shc to gp130 phosphotyrosines (8).
In BAF-BO3 murine cells transfected with various truncated cDNAs of the
human gp130 transducer, IL-6-induced survival was shown to be dependent
on STAT3 activation, whereas proliferation required both the activation
of STAT3 and the Ras/MAP kinase pathway (27). The involvement of the
Ras/MAP kinase pathway in myeloma cell proliferation is further
suggested by the inhibition of myeloma cell proliferation by MAP kinase
antisense (28). As we now find that STAT3 was also phosphorylated by
IFN- in myeloma cells, this suggests that activation of STAT3 by
either IL-6 or IFN- may be involved in inhibiting apoptosis in
myeloma cells.
This survival activity of IFN- might help to explain the conflicting
results concerning the effects of IFN on myeloma cell proliferation.
Several reports have shown that IFN- can both stimulate and inhibit
the proliferation of primary myeloma cells (4, 29, 30) or cell lines
(6, 31). In a recent study, Jelinek failed to find differences in the
levels of STAT or IFN response factor (IRF) transcription
factors in myeloma cell lines stimulated or inhibited by IFN- (7).
For U266 myeloma cells, the partial inhibitory effect of IFN on the
proliferation was associated with a partial blockage of IL-6-induced
gp130-linked SHP-2 activation and further MAP kinase activation (8). In
our IL-6-dependent myeloma cell lines, we have previously shown by
RT-PCR that there may be a weak production of the autocrine gp130
cytokines, IL-6 and/or oncostatin M (17), and IFN- increases IL-6
gene expression in XG-1 cells (6). These autocrine gp130 cytokines may
be sufficient to trigger the proliferation of myeloma cells but not
their survival, since in most cell lines, removal of exogenous cytokine
did not block entry of cells into the cycle even though the cells
progressively died. Moreover, gp130 cytokines did not significantly
contribute to the IFN--induced survival, as this activity is not
inhibited by anti-gp130 Ab. IFN- might partially inhibit the
proliferation that could be induced by autocrine gp130 cytokines,
since we have found that it can reduce the proliferation induced by
exogenous IL-6 by approximately 50%. These results add to our
understanding of the mechanism of action of IFN- and emphasize that
the survival of myeloma cells may be triggered by factors that are not
members of gp130 cytokine family.
These results might be relevant for clinical studies, as IFN- is
used in the treatment of patients with multiple myeloma. The initial
study by Mandelli et al. showed that the use of this
cytokine as a maintenance treatment increased the plateau phase and
overall survival of myeloma patients (32). However, further studies
demonstrate that the effects of IFN- are controversial (1, 33).
IFN- is also commonly used after high dose chemotherapy and
autologous hemopoietic stem cell transplantation for multiple myeloma,
but its efficacy, as assessed by randomized trials, has not been
established (34). As IFN- probably has pleiotropic effects in vivo
(35), it might activate an anti-tumoral response in some patients.
However, as our data demonstrate that IFN- can prevent apoptosis of
myeloma cells in vitro, it may also be a myeloma cell survival factor
in some patients. Such adverse effects might help to explain why
IFN- therapy was found to be associated with the development of
plasma cell leukemia in two patients (36, 37).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bernard Klein, Institut National de la Santé et de la Recherche Médicale, Unit 475, 99 rue Puech Villa, 34100 Montpellier, France. E-mail address:
3 Abbreviations used in this paper: MM, multiple myeloma; DEX, dexamethasone; HMCL, human myeloma cell lines; PI, propidium iodide; TBS-T, 138 mM NaCl, 3 mM KCl, 25 mM Tris-HCl (pH 7.4), and 0.1% Tween-20; MAP, mitogen-activated protein.
Received for publication January 26, 1998. Accepted for publication May 11, 1998.
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References |
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2B and high-dose prednisone in multiple drug-resistant multiple myeloma. Eur. J. Haematol. 43:352.[Medline]
inhibits the in vitro proliferation of human myeloma cells. Br. J. Haematol. 86:726.[Medline]
induced autocrine production of IL-6 in myeloma cell lines. J. Immunol. 147:4402.[Abstract]
: analysis of transcription factor activation and interleukin 6 receptor expression. J. Clin. Invest. 99:447.[Medline]
/ß-induced gene expression. J. Biol. Chem. 271:15862.- and interferon ß-stimulated gene expression through STAT proteins. Science 269:1721.2. Eur. J. Immunol. 26:3119.[Medline]
-interferon on human myeloma cells in a semisolid agar culture system. Scand. J. Haematol. 35:178.[Medline]
of an autocrine interleukin-6 growth loop in IL-6-dependent U266 myeloma cells by homologous and heterologous down-regulation of the IL-6 receptor - and ß-chains. J. Clin. Invest. 94:2317.
-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N. Engl. J. Med. 322:1430.[Abstract]
in the treatment of malignant hematologic diseases. Presse Med. 26:857.
. Proc. Natl. Acad. Sci. USA 91:1198. therapy. Br. J. Haematol. 79:523.[Medline]
-interferon therapy in myeloma. Br. J. Haematol. 82:631.[Medline]
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