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Departments of
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Microbiology and Immunology,
Medicine, and
Anatomy, Division of Immunobiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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1:16. For example, treatment with 10 ng/ml
anti-Fas caused 60–90% of A20 cells to undergo apoptosis in
6 h, whereas addition of FDC reduced apoptosis to background
levels (3–15%). Similarly, treatment with busulfan induced apoptosis
in 55–80% of A20 cells, whereas addition of FDC reduced B cell death
to 
15%; moreover, depletion of FDC abrogated the protective actions.
In contrast, the apoptosis-inducing effect of Adriamycin was not
reversed by FDC. The ability to block apoptosis induced by anti-Fas
or busulfan was not limited to A20 but was observed in four other
malignant pre-B cell or B cell lines. The mechanism by which FDC spare
malignant B cells from apoptosis did not involve alterations in levels
of Bcl-2, Bcl-XL, or Bax. Collectively, these data raise
the possibility that FDC may enhance tumor cell survival by protecting
malignant B cells against apoptosis induced by anti-Fas and some
but not all chemotherapeutic agents. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Currently, little information is available concerning the potential role of FDC in regulating Fas/Apo-associated or other apoptosis-related pathways in malignant lymphoid cells. However, if FDC protect malignant B cells from apoptosis, as they do in the case of their normal counterparts, it is conceivable that they might thereby promote tumor cell survival. One objective of the present study was to establish a system in which neoplastic murine B cells undergo apoptosis triggered by Fas ligation and to determine whether FDC might rescue them from apoptotic death. In this system, high levels of Fas are expressed as a result of neoplastic transformation, rather than as a consequence of Ag engagement. A second objective was to determine whether FDC may protect malignant B cells from apoptosis induced by chemotherapeutic agents. Accruing evidence indicates that many if not all antineoplastic agents, including those used in the treatment of hematological malignancies, exert their lethal effects in vitro and in vivo via an apoptotic mechanism (15, 16, 17). Recent studies suggest a link between drug-mediated apoptosis and activation of the Fas/Apo pathway (18). If such a link does in fact exist, it is plausible to propose that interference with Fas-induced apoptosis might also reduce the susceptibility of cells to cytotoxic drug-mediated cell death. Currently, no information is available concerning the possible influence of FDC on the response of neoplastic B cells to chemotherapeutic agents. Herein we report a novel finding that FDC can protect tumor cells from apoptosis induced by Fas ligation as well as by several chemotherapeutic agents. Thus, FDC may act to promote survival of malignant cells exposed to otherwise lethal stimuli.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female BALB/c mice 6 to 8 wk of age were purchased from The Jackson Laboratory (Bar Harbor, ME). The mice were housed in standard plastic shoe-box cages with filter tops. Food and water were supplied ad libitum, and the mice were used between 8 to 20 wk of age.
FDC isolation
FDC were isolated from popliteal, brachial, axillary, inguinal,
periaortic, and mesenteric lymph nodes by procedures described
previously (19) except that the mice were injected i.p.
with cyclophosphamide monohydrate ISOPAC (300 mg/kg) rather than using
exposure to ionizing irradiation to eliminate lymphocytes. FDC are
highly resistant, whereas B cells are very sensitive to
cyclophosphamide (19), rendering this drug effective in
eliminating B cells in the lymph nodes used to isolate FDC. Three days
after cyclophosphamide treatment, the lymph nodes were removed and
minced into small pieces with 26.5-gauge sterile needles to facilitate
enzyme digestion. The dissociated lymph nodes were incubated with 1 ml
of 8 mg/ml collagenase D (lot FIA148; Boehringer Mannheim,
Indianapolis, IN) and 0.5 ml of 10 mg/ml DNase I (lot 32H9545; Sigma,
St. Louis, MO) in 1 ml of DMEM at 37°C for 35 min. Then cells were
dislodged from the stroma by gentle pipetting. The media containing
free cells were collected, and the digestion was repeated to achieve
optimal release of cells from the remaining tissue. The collected free
cells were then layered directly onto a continuous Percoll gradient
(50%) and centrifuged for 20 min at 700 x g. The low
density (1.050–1.060 g/ml) FDC-enriched fraction was removed and
washed twice. Finally, the adherent cells including macrophages were
removed by incubating the cells at 37°C for 1 h. The nonadherent
cell suspension typically contained 
20–40% FDC, and this type of
FDC preparation is generally referred to simply as FDC in the figures
and text. The majority of the contaminating cells were medium to large
lymphocytes. FDC isolated by cyclophosphamide treatment contain 10%
B cells as detected by flow cytometry with PE-conjugated
anti-B220 Ab.
FDC depletion
FDC were depleted from the enriched FDC preparations by using a biotin-labeled FDC-specific mAb FDC-M1 (20, 21). FDC preparations were incubated with rat serum at 4°C for 30 min to block nonspecific Fc binding of rat mAb. Biotinylated FDC-M1 was then added, and cells were incubated for 30 min at 4°C. Cells were then washed three times before streptavidin-coupled magnetic Dynabeads (m-280, Dynal AS, Great Neck, NY) were added at concentration of 15 beads/cell in a final volume of 2.5 ml for another 30 min at room temperature. FDC bound to Dynabeads were separated by a magnetic particle concentrator (Dynal). The remaining cells represent the FDC-depleted fraction.
B cell lines and cell culture
The BALB/c-derived B lymphoma cell line A20 was cultured in RPMI
1640 supplemented with 1.0% sodium pyruvate, nonessential amino acids,
L-glutamine, gentamicin (all from Life Technologies, Grand
Island, NY), and 10% heat-inactivated FCS (HyClone, Logan, UT); all
cultures were maintained under a fully humidified atmosphere in 95%
room air, 5% CO2 at 37°C. Murine B lymphoma
cell lines WEHI 279 and M12 were provided by Dr. Daniel Conrad
(Department of Microbiology, Medical College of Virginia Campus,
Virginia Commonwealth University, Richmond, VA); pre-B cell lines Bcl-1
and 1-8 were obtained from Dr. Deborah Lebman (Cancer Center of Medical
College of Virginia Campus, Virginia Commonwealth University). These
cell lines were cultured in RPMI 1640 supplemented with 10%
heat-inactivated FCS, 2 mM glutamine, 1.0% sodium pyruvate, 10 U/ml
penicillin, 10 µg/ml streptomycin, 10 mM HEPES, and 50 µM 2-ME. The
B cells were cultured at a density of 5 x
105 cells/ml in 25-cm2
flasks or in six-well culture plates. Anti-Fas was used for 6 h to
induced apoptosis of Bcl-1 cells (100 ng/ml) and A20 cells
(anti-Fas, 10 ng/ml); Anti-Fas was used for 15 h to induced
apoptosis of WEHI 279 cells (100 ng/ml). All cell lines were cultured
with busulfan for 15 h to induce apoptosis. All cultures were
passaged three times weekly by gentle scraping to free the cells, and
the cells exhibited a doubling time of 8 h. Cell density and
viability were assessed using a hematocytometer and the trypan blue
exclusion test.
Induction of apoptosis
A20 cells were cultured at a density of 2–4 x 105 cells/ml in a 100- x 15-mm diSPO petri dish (Scientific Products, McGaw Park, IL), and cultures were typically set up in triplicate. When FDC were added, the final cell number was adjusted to be the same as the cultures without FDC so that there was a constant level of agent per cell in each condition. The A20 cells were treated as follows: various concentrations of purified hamster anti-mouse Fas mAb Jo2 (PharMingen, San Diego, CA) were added for 5–6 h to induce apoptosis (22). Cyclophosphamide monohydrate ISOPAC (Sigma, St. Louis, MO) was reconstituted in sterile water and used for 48 h; etoposide (Sigma) and Adriamycin (Bristol-Myers Squibb, New York, NY), reconstituted in sterile water, were added to the cell cultures for 6 h; busulfan (Glaxo Wellcome, Research Triangle Park, NC) was dissolved in sterile water and administered for 20 h.
TUNEL assay using FACScan analysis (23)
To detect apoptotic DNA damage induced by various agents, cultured B cells were labeled with PE-conjugated anti-mouse B220 Ab for 30 min at 4°C. Cells were then washed, fixed with 4% formaldehyde for 10 min at room temperature, and then washed twice before treatment with 0.1% Triton X-100 in 0.1% sodium citrate for 2 min on ice to permeabilize cell membranes. Cells were then incubated with TdT and FITC-conjugated dUTP (Boehringer Mannheim, Indianapolis, IN) for 1 h at 37°C. The negative control was prepared by staining with the FITC-dUTP labeling solution in the absence of TdT. The positive control was treated with DNase I (10 µg/ml, 10 min at room temperature) after permeabilization to induce DNA strand breaks and then labeled (24). Washed cells were subjected to FACScan analysis essentially as described by Piqueras et al. (24). Apoptotic cells were FITC+ manifested by increased FITC intensity, and the percentage of apoptotic B cells was determined by analyzing the PE+ population, thus ensuring that non-B cells were excluded. Consequently, the extent of apoptosis was calculated as the percentage of the PE+-FITC+ population vs the PE+-FITC- population.
Western blot analysis
Cells (107) were collected by
centrifugation and washed twice with ice-cold PBS, cell pellets were
suspended in 200 µl PBS, and the cells were lysed by adding 200 µl
2x loading buffer containing 4% SDS, 5.76 mM 2-ME, 20% glycerol,
0.1% bromphenol blue in 60 mM Tris base (pH 8.6), and sonicated. All
cell lysates were boiled for 5 min and centrifuged at 14,000 x
g for 5 min. Protein content was determined using Coomassie
protein assay reagent (Pierce, Rockford, IL). The amount of protein
added to represent each experimental group was standardized, and the
individual proteins were separated by SDS-PAGE gel (5% stacking, 12%
separating). These proteins were then transferred from the gels to
nitrocellulose membranes (Bio-Rad, Hercules, CA), and the membranes
were blocked with 5% milk/PBS-Tween for 1 h before addition of
primary Abs (rabbit polyclonal Ab to mouse Bcl-2 (1:1000), rabbit
polyclonal Ab to mouse Bcl-XL/s (1:1000), and
rabbit polyclonal Ab to mouse Bax (1:500)) and incubated at 4°C
overnight. The Abs were purchased from Santa Cruz Biotechnology (Santa
Cruz, CA) . After a thorough washing with PBS-Tween, an HRP-conjugated
secondary goat anti-rabbit Ab (Kirkegaard and Perry Laboratories,
Gaithersburg, MD) at a dilution of 1:2000 was added and incubated for
1 h at 22°C. After three washings in PBS-T, blots were developed
with a Chemiluminescence Kit (NEN Life Science Products, Boston,
MA).
Statistical methods
Data in the figures represent the mean ± SEM, and Student’s t test was used to establish whether differences were statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first sought to determine whether, and to what extent, FDC
could protect neoplastic B cells from anti-Fas-mediated
apoptosis. A20 cells treated with anti-Fas underwent apoptosis in a
dose-dependent manner, and 10 ng/ml anti-Fas was able to kill the
majority of cells within a 5-h period (data not shown). To test the
effect of FDC, A20 cells were treated with 10 ng/ml anti-Fas in the
presence and absence of FDC. In the absence of FDC, the majority of A20
cells (e.g., 60–90%) underwent apoptosis after treatment with
anti-Fas. In contrast, the level of apoptosis induced by
anti-Fas was markedly reduced in the presence of FDC (Fig. 1
A). In dose-response
studies, an FDC to B cell ratio of 1:10 fully reversed the
anti-Fas-mediated effect, but FDC to B cell ratios 1
50 were without detectable effect (Fig. 1B).
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A variety of chemotherapeutic agents were studied to assess their
ability to induce apoptosis in A20 cells. At appropriate doses,
busulfan, etoposide, Adriamycin, and cyclophosphamide all induced
apoptosis of 20–80% of the cells (data not shown). Each of these
agents was then studied to determine whether FDC might modify
lethality. Busulfan was a potent inducer of apoptosis in A20 cells, and
a majority (e.g., 55–90%) of the B cells underwent apoptosis at a
dose of 200 µg/ml (Fig. 2A).
Significantly, addition of FDC dramatically reduced apoptotic death in
busulfan-treated A20 cells (Fig. 2A). Optimal protection was
achieved at a FDC to B ratio of 1:8, although significant reductions in
apoptosis were obtained at a ratio of 1:16 (Fig. 2B). FDC
also exerted significant protection against apoptosis induced by other
agents, (e.g., p < 0.05 when compared with cells
treated with agent alone) including etoposide (Fig. 2C) and
cyclophosphamide (Fig. 2D). In contrast, FDC did not exert
discernable protective effects toward cells exposed to cytotoxic
concentrations of Adriamycin even at FDC to B cell ratios as low as 1:4
(Fig. 2E).
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The B cells that survive and emerge from germinal centers express
Bcl-2 (2). Furthermore, cell death decisions may depend on
the relative abundance of anti-apoptotic (e.g Bcl-2,
Bcl-XL) vs pro-apoptotic proteins (e.g., Bax)
(25, 26). These considerations a prompted us to determine
whether the protective actions of FDC could be attributed to induction
of Bcl-2, Bcl-XL or a decrease in Bax expression.
As illustrated by the Western blot analysis shown in Fig. 3, A20 cells expressed all of these
molecules, and contact with FDC did not substantially modify levels of
Bcl-2, Bcl-XL, or Bax proteins.
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The FDC populations used in these studies were enriched but
not pure; consequently, it remained possible that protection might
be mediated by cells other than FDC. To exclude this possibility,
FDC were removed from FDC preparations by using biotinylated FDC-M1
Ab and streptavidin-conjugated Dynabeads to generate a FDC-depleted
fraction. The FDC-depleted fraction was added to cultures in the same
ratios as the FDC-enriched population. Under these conditions,
busulfan-mediated and anti-Fas-mediated apoptoses were not
abrogated, supporting the concept that FDC are directly responsible for
antagonizing drug and anti-Fas related apoptosis in this malignant
B cell line. Fig. 4 illustrates results
obtained with busulfan, and the anti-Fas data revealed a similar
pattern (data not shown).
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To determine whether the ability of FDC to block apoptosis
represented a more general phenomenon, and not restricted solely to A20
cells, we examined four additional malignant B cell or pre-B cell
lines. Two of the lines were not susceptible to anti-Fas-mediated
killing, but all four were susceptible to busulfan-induced lethality.
In all cases in which anti-Fas or busulfan induced apoptosis, the
presence of FDC markedly reduced the killing effect (Table I).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). FDC are believed to play an important role in regulating
germinal center B cell apoptosis (1, 2, 3), and the nature of
FDC-mediated antiapoptotic activity is of great interest. Fas
expression on B cells increases after somatic hypermutation in germinal
center dark zones, and interactions with germinal center T cells
bearing Fas ligand then trigger cell death unless the B cell Ag
receptor has high affinity. High affinity B cell receptor efficiently
competes for Ag trapped on FDC, and this leads to B cell-FDC
interactions and FDC-mediated reversal of Fas-induced programmed B cell
death. To date, studies of the ability of FDC to inhibit apoptosis have
been restricted to normal B cells (1, 3, 27, 28, 29). The
present findings extend these data and indicate that a similar
phenomenon occurs in malignant B cells where apoptosis may be induced
simply by interactions with anti-Fas. In this neoplastic B cell
model, engagement of specific Ag on the FDC by the B cell does not
appear to be necessary to reverse the apoptotic signal.
It has generally been assumed that different classes of agents induce
apoptosis through distinct signaling pathways. For example, Fas ligand
and TNF-
initiate apoptosis through ligation of cell surface
receptors, leading to a cascade of events culminating in activation of
the protease cascade. In contrast, chemotherapeutic drugs are believed
to trigger the cell death process through interaction with nuclear
components such as DNA (i.e., in the case of alkylating agents,
topoisomerase inhibitors, and antimetabolites) or microtubules (i.e.,
in the case of Vinca alkaloids or taxol). The specific
sensors that detect damage to these cellular constituents and initiate
apoptotic events remain largely unknown. However, attention has
recently been focused on possible connections between chemotherapeutic
drug-induced cell death and the Fas/Apo pathway. Friesen et al.
(18, 30) provided evidence suggesting that a deficiency in
activation of the CD95 pathway could serve as the basis for drug
resistance in human leukemic cells (18). Although it is
unclear how genomic damage (i.e., by cytotoxic drugs) involves a cell
surface receptor-based system to trigger cell death, it may be
pertinent that apoptosis induced by the nuclear transcription factor
c-myc has recently been shown to be antagonized by defects
in the Fas/Apo pathway (31). It may also be relevant that
certain chemotherapeutic agents have been shown to up-regulate Fas
expression in leukemic cells (18), raising the possibility
that the Fas pathway may be involved in drug-related events. A20 cell
apoptosis induced by two alkylating agents (cyclophosphamide and
busulfan) and a topoisomerase II inhibitor (etoposide) was
substantially reversed by FDC in a manner similar to that observed in
the case of anti-Fas-induced cell death. This finding is consistent
with the concept that certain chemotherapeutic agents induce apoptosis
through engagement of at least part of the Fas pathway and further
suggests that FDC may block the cascade of drug-induced cell death
distal to its convergence with the Fas pathway.
In contrast to busulfan, etoposide, and cyclophosphamide, FDC failed to block apoptosis induced by the topoisomerase II inhibitor Adriamycin. Friesen et al. (18) have shown that high concentrations of Adriamycin do not induce Fas system expression in leukemic cells. Consequently, Adriamycin, particularly when administered at high concentrations, may utilize a pathway other than Fas/Apo to induce cell death. For example, the lethal action of Adriamycin may stem from the generations of free radicals and resulting membrane damage (32), events that may not directly involve Fas/Apo activation. In any case, this observation indicates that FDC-mediated protection against drug-induced apoptosis is very likely pathway specific.
The mechanism(s) by which FDC protect malignant B cells from apoptosis has (have) not been established. It is known that B cells selected to emerge from normal germinal centers express Bcl-2, and Bcl-2 is found in follicular lymphomas which are characterized by the presence of FDC (33, 34). Also, cell death decisions may depend on the relative abundance of antiapoptotic (e.g., Bcl-2, Bcl-XL) vs proapoptotic proteins (e.g., Bax) (26). These considerations prompted us to determine whether contact with FDC resulted in induction of Bcl-2, Bcl-XL, or a decrease in Bax expression. The data revealed that all of these molecules were present in A20 cells, but contact with FDC did not substantially modify levels of Bcl-2, Bcl-XL, or Bax protein Thus, it appears unlikely that the cytoprotective activity of FDC stems from altering the relative abundance of pro- and antiapopotic proteins. We cannot, however, presently rule out the possibility that FDC act by modifying interactions between these proteins, i.e., by reducing levels of the free Bax (35). In preliminary studies, we sought to explore the possibility that FDC might block apoptosis induced through the mitochondrial pathway. Staurosporine is known to induce apoptosis through this pathway (25), and FDC antagonizes the ability of staurosporine to induce apoptosis (Tew et al., unpublished observations). Furthermore, the level of active caspase 9 (caspase 9 p10) was reduced when FDC were added to staurosporine-treated cells. Thus, these data suggest that FDC can interfere with apoptosis induced through a pathway linked to mitochondrial function, a possibility that is currently under investigation. It also appears that cell membrane-associated molecules are important in the mechanism used by FDC to rescue B cells from an apoptotic death. Experiments were done using transwell culture chambers with 0.3-µM pore size Nucleopore membranes that allows rapid diffusion of medium between upper and lower chambers while keeping cells separated. The addition of anti-Fas to these cultures caused apoptosis in the tumor cells, but an FDC effect was not detectable when FDC were confined to the upper chamber and A20 cells were confined to the lower chamber (e.g., 72 ± 3% apoptosis with A20 cells alone vs 71 ± 7% apoptosis in the A20 cells when FDC were present in the upper chamber). These data suggest that FDC-B cell contact and membrane-associated molecules are an important part of the mechanism used by FDC to rescue B cells from apoptotic death. In a recent study, we found that CD21L on the FDC engaged CD21 on the B cell, leading to optimal Ab production and that these membrane molecules many be important in delivering the survival signal (7). This possibility is supported by recent data indicating that B cells lacking CD21 do not survive well in germinal centers (36).
The results reported here raise an issue that has potential clinical significance. For example, FDC are abundant in non-Hodgkin’s lymphomas derived from the follicular center or the mantle zone, where they interact with and support the survival of these malignant B cells (37). Furthermore, chemotherapeutic drugs kill many cells in secondary lymphoid tissues, including some germinal center B cells, and this may allow tumor cells to enter normal lymphoid follicles and interact with FDC. Based on the present findings, FDC-associated malignant B cells could theoretically escape apoptosis triggered by certain chemotherapeutic agents and cytotoxic T cells that utilize Fas ligand for killing. Thus, a possible implication of these findings is that FDC could provide a mechanism by which malignant lymphoid cells escape the lethal effects of some chemotherapeutic agents and cytotoxic T cells. In vivo studies designed to test this hypothesis are currently in progress.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. John G. Tew, Department of Microbiology/Immunology, P.O. Box 980678, MCV Station, Richmond, VA 23298-0678.
3 Abbreviation used in this paper: FDC, follicular dendritic cells.
Received for publication June 7, 1999. Accepted for publication September 28, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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