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(Journal of Leukocyte Biology. 2003;73:363-368.)
© 2003 by Society for Leukocyte Biology

Cross-talk between tumor cells and neutrophils through the Fas (APO-1, CD95)/FasL system: human glioma cells enhance cell viability and stimulate cytokine production in neutrophils

Wei-Shio Hor, Wei-Lune Huang, Yee-Shin Lin and Bei-Chang Yang

Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Correspondence: Bei-Chang Yang, Ph.D., Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. E-mail: y1357{at}mail.ncku.edu.tw


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ABSTRACT
 
Many tumor cells are resistant to Fas-mediated killing, which has been primarily used as a mechanism to evade immune attack. In this study, we found a new action of Fas on tumors where activation of the Fas signal may force tumor cells to produce survival factors for neutrophils. Human peripheral circulating neutrophils in coculture with glioma cells showed significant delays in spontaneous apoptosis. Interleukin (IL)-6 and IL-8 partially mediated the glioma cell-associated, protective effect on neutrophils. The Fas agonistic antibody CH-11 dose-dependently stimulated the expression of IL-6 and IL-8 in glioma cells. Accordingly, blocking the Fas/FasL interaction reduced IL-6 and IL-8 production in glioma cells and impaired their protective effect on neutrophils. Coculture with glioma cells also affected the expression of cytokines in neutrophils, including IL-8, interferon-{gamma}, and tumor necrosis factor {alpha} to various extents. Collectively, our results demonstrate bi-directional cross-talk between tumor and immune cells. Although Fas activation alone cannot induce apoptosis in tumor cells, it may potentially initiate an effective anti-tumor response through a circumvented mechanism.

Key Words: apoptosis • IL-6 • IL-8


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INTRODUCTION
 
When a Fas receptor (Fas, APO-1, CD95) engages with its ligand (FasL), a caspase cascade is initiated, which in most cases, leads to apoptosis of Fas+ cells. Decreased susceptibility to Fas-mediated apoptosis has been implicated in tumorigenesis [1 2 3 ]. Moreover, FasL is expressed in tumor cells and is able to inactivate reactive T cells, which has been termed a Fas-counterattack mechanism [3 4 5 6 ]. However, using FasL+ cells for organ transplantation or ectopic expression of FasL in transgenic animals caused severe tissue destruction [7 , 8 ], which indicates a much subtler interaction of Fas and FasL in vivo than has previously been perceived. Accumulating data indicate that the Fas signal may modulate gene expression in addition to its well-known death-triggering capability. In the immune system, responses to Fas activation vary with cell types and their differentiation stages. FasL costimulates the proliferation of CD8+ T cells and resting T lymphocytes by augmenting interleukin (IL)-2 production [9 , 10 ]. Fas engagement induces maturation of dendritic cells (DC) to release IL-1ß and interferon-{gamma} (IFN-{gamma}) during DC–T cell cognate interactions [11 ]. Moreover, Fas-mediated apoptosis of lymphoid cells leads to the rapid production of IL-10 in these cells, which is probably responsible for deviations in the immune response after antigen presentation [12 ]. Thus, the interplay between FasL+ tumors and immune cells deserves re-evaluation in a context without extensive apoptosis.

Recently, we found that the expression of FasL on gliomas or melanomas caused an accumulation of neutrophils in tumor sites, and this was associated with a reduction in tumorigenesis and metastasis [13 , 14 ]. Gliomas are one of the common tumors in the central nervous system, and they express high levels of FasL [15 , 16 ]. Increased numbers of circulating neutrophils and significant neutrophil infiltration into tumor tissues are seen in glioma patients [17 ]. It is possible that contact between glioma cells and neutrophils may directly or indirectly affect the number of circulating neutrophils and influence their infiltration into the tumor. This contention is supported by the finding that Fas activation of resident peritoneal macrophages by syngeneic FasL+ tumor cells in vivo induced the production of chemokines in these macrophages [18 ]. In this study, we further address questions of the Fas signal and the mutual interaction between tumor cells and neutrophils by using an in vitro coculture system. Our results show that when in contact with human glioma cells, spontaneous apoptosis in peripheral circulating neutrophils was reduced as a result of elevated levels of IL-6 and IL-8 in the culture media. Furthermore, we demonstrate that glioma cells produce these survival factors upon the activation of Fas.


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MATERIALS AND METHODS
 
Cells and treatments
Human peripheral circulating neutrophils were isolated from heparinized venous blood obtained from healthy volunteers using a Percoll gradient (63–69%) as described previously [19 ]. In brief, 5 ml 63% Percoll was underlayered with 5 ml 69% Percoll (Sigma Chemical Co., St. Louis, MO). Each 5 ml blood sample was overlayered on the gradient and centrifuged at 450 g for 25 min. Harvested neutrophils were washed once with phosphate-buffered saline (PBS), and residual erythrocytes were subjected to hypotonic lysis. Neutrophils and Jurkat cells were cultured in RPMI-1640 medium (Gibco-BRL Life Technologies, Grand Island, NY) supplemented with 10% fetal bovine serum (FBS), and incubated at 37°C in a humidified atmosphere (5% CO2).

Glioma cell lines U-373MG and U-118MG were obtained from the American Type Culture Collection (Manassas, VA). U-373MG(R) and U-118MG(R), expressing reduced levels of FasL, were established from U-373MG and U-118MG, respectively, by transfecting a plasmid, which codes for a FasL-specific ribozyme (FasLribozyme) [13 ]. U-373MG(V) and U-118MG(V) carry the pEGFP-N1 plasmid and served as the nonribozyme controls in this study. Glioma cells were routinely maintained in 10% FBS/Dulbecco’s modified Eagle’s medium (DMEM; Gibco-BRL) and were then transferred to RPMI-1640 medium for the coculture experiments. Neutrophils harvested from coculture experiments were routinely checked under a fluorescent microscope to ensure no contamination of glioma-derived cells, which are enhanced green fluorescent protein (EGFP)-positive and which emit green light under UV excitation [13 ]. To demonstrate the requirement of cell-to-cell contact, glioma cells (3x105) and neutrophils (2x105) were cultured together in a chamber or separately in different chambers in wells of a 0.4-µm pore size Transwell plate for 24 h (six wells; Costar GmbH, Bodenheim, Germany). Glioma cell-conditioned media of 48 h cultures were also used to treat neutrophils. The mouse monoclonal antibody, ZB-4 (an antagonistic antibody recognizing the Fas receptor; purchased from Upstate Biotechnology, Lake Placid, NY), at a concentration of 500 ng/ml was used to block the engagement of Fas and FasL. Antibodies for IL-6 and IL-8 (both from R&D Systems, Minneapolis, MN) at a concentration of 500 ng/ml were used to neutralize IL-6 and IL-8 in the culture media.

Reverse transcriptase-polymerase chain reaction (RT-PCR)
Total RNA was prepared using the RNeasy kit following the manufacturer’s instructions (Qiagen, Hilden, Germany). Synthesis of cDNA was performed with oligo-dT as a primer and StrataScripTM-H RT in the presence of RNasin (Stratagene, La Jolla, CA). RT-PCR on IL-6, IL-8, IFN-{gamma}, tumor necrosis factor {alpha} (TNF-{alpha}), Fas, and FasL genes was performed as described previously [20 21 22 ]. The generated cDNA was subjected to PCR amplification in a DNA thermal cycler (Hybaid Omnigene, Middlesex, UK). ß-Actin served as a quantitative control. PCR products were fractionated by agarose electrophoresis, stained with ethidium bromide, and visualized under UV light.

Detection of apoptotic cells
Neutrophils and glioma cells cultured alone, treated with the Fas-agonistic antibody CH-11 (purchased from Upstate Biotechnology), or grown in coculture together were separately harvested at certain intervals. Apoptotic cells were stained by propidium iodine (PI) and appeared as a subG0 population in flow cytometric analysis. In brief, cells were washed once in ice-cold PBS, fixed in ice-cold 70% ethanol, and then stored at -20°C for 24 h. After being washed with PBS, cells were stained in a solution containing 0.5 ml RNase (1 mg/ml; Sigma Chemical Co.) and 0.5 ml PI (500 µg/ml) for 30 min in the dark. Apoptosis in Jurkat cells was trigged by CH-11 at a concentration of 10 ng/ml and served as the positive control for Fas-mediated apoptosis. In addition, apoptosis was also determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay in some experiments. Cells were fixed with 1% paraformaldehyde in PBS for 10 min at room temperature and were then incubated in 70% ethanol at -20°C for 24 h. The percentage of apoptotic cells was assessed using the ApopAlert DNA fragmentation assay kit (Clontech Laboratories, Palo Alto, CA) according to the manufacturer’s instructions and was then analyzed by flow cytometry.

Statistical analysis
Between-group comparisons were performed using Student’s t-test. Values with P < 0.05 were considered significant.


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RESULTS
 
Prevention of spontaneous apoptosis in neutrophils by coculture with glioma cells
When neutrophils were isolated and cultured in vitro, spontaneous apoptosis rapidly occurred, and the PI-stained subG0 cell population increased with time. In general, 30–50% of neutrophils became apoptotic by in vitro culture for 2 h and 65% for 4 h, reaching 70–90% in 12–24 h. Apoptosis in neutrophils was significantly delayed by coculturing with U-118MG derivatives (Fig. 1A ). Glioma cells expressing a lower level of FasL, i.e., U-118MG(R), exhibited a better protective effect on neutrophils. The same results were obtained when apoptosis was measured by the TUNEL assay followed by flow cytometric analysis (Fig. 1B) . Similarly, apoptosis in neutrophils was significantly reduced by coculturing with U-373MG-derived cells (P<0.01; Fig. 1C ). We then investigated whether soluble factors mediate this glioma-associated, protective effect (Fig. 2 ). Conditioned media of different glioma cell lines could delay the spontaneous apoptosis in neutrophils obtained from two healthy individuals, but the media were much less effective than using direct coculture. Moreover, avoidance of cell-to-cell contact by culturing glioma cells and neutrophils in different chambers of a Transwell, where soluble factors could pass through a permeable membrane in between, also hampered the survival of neutrophils.



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  		Figure 1. Coculture with human glioma cell lines enhanced the survival of human circulating neutrophils. Neutrophils were purified from peripheral blood of healthy donors and cultured for 24 h in the presence or absence of glioma cells. Apoptotic cells were detected by PI staining and appeared as a subG0 population in flow cytometric analysis or were detected using the TUNEL assay. (A) Representative histograms showing the subG0 population of neutrophils stained by PI. (B) Representative histograms showing TUNEL-positive neutrophils. The percentages of apoptotic cells are indicated in parentheses. A, Fresh neutrophils; B, neutrophils cultured in vitro for 24 h; C, neutrophils in coculture with U-118MG(V) for 24 h; D, neutrophils in coculture with U-118MG(R) for 24 h. (C) Enhanced survival of neutrophils was also observed in coculture with U-373MG derivatives. Each point shown is the percentage of apoptotic neutrophils detected for an individual person. Mean values of the groups are given in parentheses. Mn, mean; Cv, coefficient of variation; Gm, geometric log means.



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  		Figure 2. Improved survival of neutrophils by glioma cells requires cell-to-cell contact. Percentages of the subG0 population in neutrophils of two healthy individuals were determined by PI staining. 0 h, Fresh neutrophils; 24 h, neutrophils cultured in vitro for 24 h; U-118MG(V or R), neutrophils cultured with U-118MG(V or R) together for 24 h; 1/2-U118MG(V or R)CM, neutrophils cultured with U-118MG(V or R)-conditioned medium that had been diluted twofold with fresh medium; U-118MG(V or R)-CM, neutrophils cultured with U-118MG(V or R)-conditioned medium; T(V or R), U-118MG(V or R) cultured in the lower well and neutrophils in the upper well of a six-well Transwell plate. Values shown are the average of duplicate experiments.

Cytokine production in glioma cells and neutrophils
It has been reported that human glioma cells express IL-8 upon Fas activation [23 ]. IL-8 is a potent chemoattractant and activator of neutrophils [24 , 25 ]. RT-PCR for IL-6 and IL-8 genes was performed to determine whether they are involved in the glioma cell-associated, protective effect. Glioma cells expressed low levels of IL-6 and IL-8 (Fig. 3A , lanes 1 and 2). The basal expression of IL-8 in U-118MG(V) was slightly higher than that in U-118MG(R). Transcriptions of IL-8 and IL-6 in U-118MG-derived cells were enhanced by coculturing with neutrophils. IL-8/IL-6 induction in U-118MG(R) was more profound than that in U-118MG(V; Fig. 3A , lanes 3 and 4). In addition, transcripts of IL-6, IL-8, IFN-{gamma}, TNF-{alpha}, Fas, and FasL genes in neutrophils were determined. Fresh neutrophils expressed Fas and FasL but not IL-8, IFN-{gamma}, or TNF-{alpha} (Fig. 3C , lane 1). A 24-h coculture with glioma cells augmented the expression of IL-8 in neutrophils (Fig. 3C , lanes 2 and 3). In addition, U-118MG(V) induced more IFN-{gamma} and TNF-{alpha} in neutrophils than did U-118MG(R). Levels of Fas and FasL in neutrophils were not changed under the culture conditions used in this study. Neutrophils did not express IL-6 (data not shown).



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  		Figure 3. Cytokine production in glioma cells and neutrophils. (A) Fas-dependent cytokine production in U-118MG. U-118MG derivatives were treated with CH-11 (200 ng/ml) or by coculturing with neutrophils for 24 h. Fas was blocked by preincubation of glioma cells with ZB-4 (500 ng/ml) for 1.5 h. (B) Induction of IL-6 and IL-8 in glioma cells by CH-11. U-118MG derivatives were treated with CH-11 for 24 h. (C) Gene expression in neutrophils. Neutrophils and U-118MG derivatives were cultured together for 24 h. Neutrophils were separately harvested, and the transcripts of IL-8, IFN-{gamma}, TNF-{alpha}, Fas, and FasL in those cells were detected by RT-PCR.

We further analyzed the association between IL-6/IL-8 expressions and Fas signaling. The Fas receptor was activated by CH-11, an agonistic antibody directly initiating a Fas signal, or was blocked by ZB-4, an antagonist antibody able to prevent the engagement of Fas and FasL. In a preliminary experiment using neutrophil/glioma coculture, we found that the degree of apoptosis in neutrophils was higher in the presence of the ZB-4 antibody than in its absence, suggesting a positive role of the Fas signal for glioma-associated cell protection. Upon CH-11 treatment at up to 200 ng/ml, few apoptotic glioma cells were observed (data not shown). Yet, CH-11 stimulated IL-6 and IL-8 in glioma cells in a dose-dependant manner (Fig. 3B) . Fas ligation by CH-11 induced a higher level of IL-6 with U-118MG(R) than with U-118MG(V). When glioma cells were treated with the ZB-4 antibody (500 ng/ml) for 1.5 h to cap the Fas molecules, the basal expressions of IL-6 and IL-8 in glioma-derived cells U-118MG(V) and U-118MG(R) were reduced (Fig. 3A , lanes 5 and 6). Particularly, IL-6 and IL-8 in the Fas-precapped U-118MG(V) were significantly reduced, as both were CH-11-treated and were in coculture with neutrophils (Fig. 3A , lanes 7–10).

Neutralization of IL-6 and IL-8
To further assess the role of IL-6 and IL-8 in glioma-associated protection, we applied antibodies to neutralize IL-6 and IL-8. Neutralization of IL-6 or IL-8 did not worsen the spontaneous apoptosis in neutrophils cultured alone in vitro. In coculture with glioma cells, apoptosis in neutrophils was elevated upon neutralization of IL-6 and IL-8 in the coculture media (Fig. 4 ). Neutralizing IL-6 or IL-8 by 500 ng/ml corresponding antibody partially reduced the viability of neutrophils in coculture with glioma cells (P<0.01). When IL-6 and IL-8 were neutralized, viable neutrophils in coculture were further reduced to ~10%, a level similar to those neutrophils cultured alone in vitro for 24 h (P<0.01).



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  		Figure 4. Neutralization of IL-6 and IL-8 by antibodies abrogated the protective effect of glioma cells on neutrophils. Neutrophils were purified from healthy donors and cultured for 24 h in the presence or absence of U-118MG(R). IL-6 and IL-8 in the coculture media were neutralized by applying corresponding antibodies (Ab) at a concentration of 500 ng/ml. Apoptotic cells were detected by PI staining and appeared as the subG0 population in flow cytometric analysis.

Partial association of the protective effect with the Fas signal
As glioma cells and neutrophils express the Fas receptor, it is of interest to know which one is mainly responsible for the enhanced survival of neutrophils in coculture. To determine this, we initially incubated neutrophils or glioma cells with ZB-4 to cap their Fas molecules. After washing off the excess antibody with fresh DMEM medium, these Fas-capped cells were used for coculturing (Fig. 5 ). Application of ZB-4 was unable to rescue neutrophils cultured in vitro from spontaneous apoptosis, in that 90% of ZB-4-treated cells died within 24 h. Preincubation of neutrophils with ZB-4 for 1.5 h did not significantly alter the protective effect of glioma cells in coculture. In contrast, a reduced, protective effect on neutrophils was observed by coculturing with ZB-4-pretreated glioma cells (P<0.01).



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  		Figure 5. Blockage of Fas/FasL engagement abrogated the protective effect of glioma cells on neutrophils. Neutrophils were purified from healthy donors. Apoptosis was determined in neutrophils treated with the ZB-4 antibody and cultured in vitro for 1.5 and 24 h [ZB-4(1.5h) and ZB-4(24h), respectively]. U-118MG(R), Neutrophils cocultured with U-118MG(R) for 24 h. (N+ZB-4)+U-118MG(R), Neutrophils pretreated with ZB-4 for 1.5 h and then subjected to coculture with U-118MG(R) for another 22.5 h. ZB-4+U-118MG(R), U-118MG(R) pretreated with ZB-4 for 1.5 h; then, neutrophils were added and incubated for a further 22.5 h. Apoptosis in neutrophils was detected by PI staining and appeared as the subG0 population in flow cytometric analysis.


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DISCUSSION
 
Human neutrophils cultured in vitro undergo rapid apoptotic cell death. Although mature neutrophils coexpress Fas and FasL [26 , 27 ], spontaneous apoptosis in neutrophils obviously occurs through a Fas-independent pathway, as agonistic or antagonistic antibodies specific for Fas failed to modify the death rate. The rapid apoptosis in neutrophils is probably a result of a lack of essential growth factors, which only exist in human serum. It is interesting that this spontaneous apoptosis of neutrophils was significantly delayed in coculture with glioma cells with no supplementation of human sera. Conditioned media of glioma cells also protected neutrophils from death but with much less potency than that with direct cell-to-cell contact. Neutralization of IL-6/IL-8 using antibodies that reduced the viability of neutrophils in coculture conditions indicates that this glioma cell-associated, protective effect is mediated at least in part through IL-6/IL-8. Our results confirm this notion described previously and our own data that IL-6 and IL-8 can prolong the lifespan of human neutrophils in vitro by delaying apoptosis (refs. [28 29 30 ], and data not shown). Moreover, the expressions of IL-6 and IL-8 in glioma cells upon contact with neutrophils provide an explanation for the elevated number of circulating neutrophils and increased tumor neutrophil infiltration in patients with gliomas [17 ].

IL-6/IL-8 in the coculture media might be generated from two sources: by glioma cells and from neutrophils. Direct Fas ligation by CH-11 induced the expression of IL-6/IL-8 in glioma-derived cells. When FasL of glioma cells was down-regulated by FasLribozyme, which decreases the engagement of Fas and FasL on the same glioma cells in an autocrine or paracrine way, the basal expression of IL-6/IL-8 in glioma cells was concomitantly reduced. Moreover, inactivation of Fas by the antagonistic antibody ZB-4 inhibited not only CH-11-induced but also neutrophil-induced IL-6/IL-8 expression in glioma cells. Our findings are in agreement with the report that Fas signaling leads to the expression of chemokines in human glioma cells [23 ].

Neutrophils expressed little IL-8 when they were cultured alone in vitro. The transcription of IL-8 in neutrophils was enhanced by coculturing with glioma cells. The induction of IL-8 in neutrophils not being correlated with the levels of FasL on glioma cells suggests that it was being driven through a Fas-independent pathway. Although the capping of Fas on glioma cells could attenuate the protection, the capping of Fas on neutrophils had little effect. Thus, Fas signaling in glioma cells, when it is initiated by the FasL on neutrophils, mainly mediates the production of survival factors. Conversely, coculturing with glioma cells also induced IFN-{gamma} and TNF-{alpha} in neutrophils, and this occurred in positive correlation with the amount of FasL on tumor cells. TNF-{alpha} is an inflammatory cytokine that accelerates neutrophil apoptosis [31 , 32 ]. Accordingly, neutrophils survive better in coculture with glioma cells having a low level of Fas-L, probably because they trigger less TNF-{alpha}.

Great interest has recently been generated by the possibility that the Fas–FasL system may represent one of the tools used by tumor cells to evade immunologic control [3 4 5 6 ]. In this study, we provide evidence that the immune system can develop strategies to control tumor cells using bi-directional cross-talk through the Fas–FasL system. Although the ligation of Fas on tumor cells did not cause the cells to die, it did potentially enhance the immune reactions by providing survival factors for immune cells, such as IL-6/IL-8, for neutrophils as demonstrated in this study. IL-6 secretion by a rat T9 glioma induced a neutrophil-dependent anti-tumor response [33 ], suggesting that activating the Fas signal in tumor cells may be beneficial for tumor management. A pivotal role of neutrophils in combating tumors has previously been recognized in several tumors. The action of tumor-suppressive T helper cell type 1 cells through CpG DNA is granulocyte-dependent [34 ]. Deletion of granulocytes in mice significantly increases the susceptibility of lung metastasis of FasL+ melanomas [14 ]. Collectively, our results can help to further interpret previous findings that expression of Fas in lung cancer correlates with a good prognosis [35 ] and suppressed metastasis [36 ]. Consequently, a better understanding of the physiological and pathological roles of the Fas–FasL interaction during tumor progression will help in the design of effective anti-tumor responses.


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ACKNOWLEDGEMENTS
 
This work was supported by grants from the National Science Council, Taiwan (NSC89–2320-B006–020), and the MOE Program for Promoting Academic Excellence of Universities from the Minister of Education (91-FA09–1-4) to B-C. Y.

Received July 28, 2002; revised December 3, 2002; accepted December 5, 2002.


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