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(The FASEB Journal. 2000;14:661-668.)
© 2000 FASEB

Tumor cell-derived prostaglandin E2 inhibits monocyte function by interfering with CCR5 and Mac-1

REINHARD ZEIDLER1, MIKLOS CSANADY2, OLIVIER GIRES, STEPHAN LANG, BÄRBEL SCHMITT and BARBARA WOLLENBERG

Department of Otolaryngology, University of Munich, 81377 Munich, Germany

1Correspondence: Department of Otolaryngology, University of Munich, Marchioninistr. 15, 81377 Munich, Germany. E-mail: rzeidler{at}hno.med.uni-muenchen.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The cyclooxygenases (COX)-1 and COX-2 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids. Whereas COX-1 is expressed ubiquitously, COX-2 is an immediate-early gene often associated with malignant transformation, and a role for the COX enzymes in tumor initiation and promotion is discussed. Nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin and indomethacin that block COX-1 and -2 have been shown to have beneficial effects for tumor patients. Therefore, these compounds have gained interest also among oncologists. However, the molecular mechanism by which NSAIDs inhibit carcinogenesis is not clearly understood. The prostaglandin-dependent and -independent effect may both account for their antineoplastic action. We show here that tumor cells derived from different tumors regularly produce prostaglandin E2 (PGE2) interfering with the function of monocytes. In particular, PGE2 inhibits the potential of monocytes to migrate in the direction of a chemotactic stimulus and to adhere to endothelial cell. This inhibition is most probably due to a modulation of the chemokine receptor CCR5 and the ß2-integrin Mac-1. Both down-regulation of CCR5 and reduced expression of Mac-1 may diminish the potential of peripheral blood monocytes to leave blood vessels and invade target tissues. Since both dysfunctions can be restored with NSAIDs, our findings help to explain the molecular chemopreventive action of NSAIDs on tumor formation and progression.—Zeidler, R., Csanady, M., Gires, O., Lang, S., Schmitt, B., Wollenberg, B. Tumor cell-derived prostaglandin E2 inhibits monocyte function by interfering with CCR5 and Mac-1.


Key Words: immune evasion • prostaglandins • migration • adhesion


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE CYCLOOXYGENASES (COX)-1 and COX-2 are key enzymes of the biosynthetic pathway of prostanoid formation. Both COX-1 and COX-2 are blocked by nonsteroidal anti-inflammatory drugs (NSAIDs) (1) . Whereas COX-1 is constitutively expressed in many tissues (2) , COX-2 is an immediate-early gene that is induced in inflammatory cells by mitogens, tumor promoters, and cytokines. The cyclooxygenases have become of special interest to oncologists since overexpression of COX-2 was demonstrated in human tumors (3) and epidemiological studies revealed that continuous use of NSAIDs reduces the risk of development of different cancers (4 , 5) . A causative role for the COX enzymes in tumor development and progression as well as metastatic behavior has also been demonstrated (6 7 8) . Since elevated prostaglandin E2 (PGE2) levels occur in various cancers (9 , 10) , inhibition of the COX isoenzymes is probably an important function of NSAIDs (11 12 13) . However, PGE2-independent effects have also been described (4 , 14 15 16) , and the molecular mechanisms of the chemopreventive antineoplastic action of NSAIDs remain unclear. For a summary of COX-dependent and independent NSAIDs actions, we refer to a recently published review (17) .

Leukocytes that circulate in the body have to exit the bloodstream in order to exert their immunological function. Leukocytes adhere to endothelial cells at the luminal side of blood vessels, transmigrate, and enter target tissues (18) . Adhesion is a complex process that involves a plethora of different molecules like the ß2-integrins (CD11a/CD18; CD11b/CD18, and CD11c/CD18) (19) . The pivotal immunological significance of ß2-integrins is obvious from leukocyte adhesion deficiency type I (LAD-I), a clinical condition caused by a mutation in the ß2 common CD18 chain. Patients suffering from LAD-I usually die at a young age due to multiple leukocyte defects (20) .

Chemokines are small proteins that function as emergency signals produced locally in response to inflammation and immune responses (21) . Chemokines induce chemotaxis of leukocyte subsets and stimulate their adhesion to the endothelium (22) . Chemokines signal through specific seven-transmembrane domain, G-protein-coupled receptors (23) . CCR5, one of these receptors, is expressed on monocytes and certain lymphocytes, and binds macrophage inflammatory protein alpha (MIP1{alpha}), MIP1ß, and RANTES (24) . CCR5 garnered special interest when it was identified as the fusion cofactor for macrophage-tropic HIV (25) . The physiological role of CCR5 in activation and migration of monocytes, however, has been studied much less.

Only recently it has been demonstrated that PGE2 down-regulates CCR5 surface expression on monocytes, rendering these cells resistant to HIV (26) . Since the COX isoenzymes are often overexpressed in human tumors and PGE2 is the major metabolite of arachidonic acid metabolism, we asked whether tumor-derived PGE2 interferes with the physiological activity and function of monocytes. We show here that PGE2 derived from human carcinoma cell lines causes down-regulation of the surface expression of CCR5 and the adhesion molecule Mac-1 on monocytes. Down-regulation results in a reduced competence of monocytes to respond to a chemoattractant (MIP-1ß) and to adhere to endothelial cells. In addition, conditioned tumor supernatants induce the high level production of interleukin 10 (IL-10) and tumor necrosis factor {alpha} (TNF-{alpha}) in monocytes. These effects can be inhibited by the NSAIDs aspirin and indomethacin. Since adhesion and migration are also pivotal steps in the recruitment of effector cells into the tumor stroma and the subsequent eradication of tumor cells (27) , their inhibition may have implications on tumor development. Our findings provide a new molecular explanation for the beneficial effects of aspirin and indomethacin on tumor incidence and may have clinical consequences for the treatment of cancer patients.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cell lines, cytokines, and PGE2
FaDu (HTB-43; ATCC, Manassas, Va.) and PCI-1 (a gift of Dr. T. Whiteside, Pittsburgh, Pa.) are cell lines derived from squamous cell carcinoma of the head and neck, and GHD-1 is a permanent cell line derived from a hypopharynx carcinoma that was established in our laboratory. MCF-7 (HTB-22; ATCC) is a human mammary carcinoma and HCT-8 (CCL-244; ATCC) is a human colon carcinoma cell line. All cell lines used were maintained as continuously growing monolayers in DMEM with 10% fetal calf serum (FCS) (both from Seromed, Berlin, Germany). Recombinant human TNF-{alpha} and IL-10 were from Boehringer Mannheim (Mannheim, Germany); PGE2 was from Sigma (Munich, Germany).

Generation of cell-free tumor cell supernatants
Tumor cells were seeded at 105 cells/ml and grown for 2 days in DMEM at 37°C. Supernatants were harvested, centrifuged, and passed through a 0.2 µm Acrodisc low protein binding filter (Gelman Sciences, Ann Arbor, Mich.). IL-10, TNF-{alpha}, and PGE2 production was determined with commercial ELISA assay (R&D Systems; Wiesbaden, Germany) according to the manufacturer’s instructions. PGE2 production given in Table 1 represents the mean of three different experiments (SD <20%).


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  		Table 1. PGE2 production in various tumor cell supernatants and their effects on CCR5 and Mac-1 expression on monocytes as observed by FACSa

FACS analysis
For FACS analysis, 105 cells were incubated with the primary antibody for 30 min on ice in phosphate-buffered saline (PBS)/5% FCS. The cells were washed twice in PBS and incubated for another 30 min with the second FITC-labeled antibody. After two final washings, propidiumiodide was added and flow cytometry was performed using a FACSCalibur cytometer and the CellQuest analysis program (Becton Dickinson, Heidelberg, Germany).

Adhesion assay
For monocyte adhesion, peripheral blood monocytes were incubated for 2 days in either DMEM or 100% conditioned tumor cell supernatants. Primary endothelial cells from umbilical blood cords (10,000 cells/per well) were seeded in 96-well plates at half-confluency and kept for 2 days in endothelial cell growth medium (Promocell, Heidelberg, Germany). After 2 days, endothelial cells had reached confluency. Monocytes were labeled for 30 min at 37°C with 20 µM of the fluorochromic dye CMFDA (Molecular Probes, Eugene, Oreg.) and washed twice; 2 x 104 monocytes were than added to the endothelial cell layer for 30 min to promote adherence. Plates were washed three times and supernatant was almost completely removed. The 96-well plate was then covered, inverted, and centrifuged for 10 min at 500 g at room temperature. The number of adhering monocytes was determined by measuring fluorescence at 525 nm in a Wallac 1420 Victor multilabel counter (Wallac, Turku; Finland). For adhesion to recombinant human intercellular adhesion molecule 1 (ICAM-1), 293 cells were transfected with an expression plasmid encoding a fusion protein of the Fc part of a human immunoglobulin (IgG1) and ICAM-1 (Fc/ICAM-1; a generous gift of Dr. W. Kolanus, Munich) and supernatants were collected 4 days after transfection. Culture dishes (Falcon 1008) were first coated for 1.5 h with a human IgG-specific antibody (5 µg/ml; Dianova, Hamburg; Germany) in 50 mM Tris-Cl, pH 9.4 and then for 4 h at room temperature with the supernatant from transfected 293 cells. Dishes were washed twice to remove unbound ICAM-1 and monocytes were added for 2 h. After two final washings, adherent cells were trypsinized and counted.

Monocyte migration
For cell migration assays, 2 x 106 monocytes were precultivated for 1 day in either DMEM or 100% conditioned FaDu-SN. Monocytes were then placed on 8 µm pore size polycarbonate filters (Nunc, Roskilde, Denmark) and allowed to transmigrate for 4 h in the direction of MIP1ß (20 ng/ml; R&D Systems, Heidelberg, Germany) in the lower chamber. Migrated cells were pelleted, stained with Giemsa black, and counted under light microscopy. Mean values of migrated cells were calculated from 3 wells/supernatant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Tumor cell supernatants induce the production of IL-10 and TNF-{alpha}
Tumor samples derived from head and neck cancer and other locations, as well as permanent tumor cell lines, have been shown to produce PGE2 (28 29 30) . Most of the tumor cell lines we used for our investigations also produce PGE2 (Table 1) . Since PGE2 induces IL-10 production (30) , we first asked whether these tumor cell lines also synthesize this immunosuppressive cytokine. ELISA assays performed with conditioned tumor cell supernatants (Tu-SN), however, revealed that none of these cancer cell lines produce detectable amounts of IL-10 (Fig. 1 ). The fact that IL-10 synthesis has been described in freshly excised tumors (31 32 33) prompted us to investigate whether these tumor cells induce IL-10 production in primary peripheral blood monocytes. Therefore, cultivated monocytes were kept in conditioned tumor supernatants or DMEM cell culture medium for 2 days. Monocytes per se produce only small amounts of IL-10 but synthesis of this cytokine was dramatically induced by cultivation of monocytes in tumor supernatants for 2 days (Fig. 1) .



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  		Figure 1. Supernatants of tumor cell lines derived from head and neck, breast, and colon cancer induce IL-10 and TNF-{alpha} production by primary monocytes. All tumor cell lines tested neither produced IL-10 nor TNF-{alpha} per se, and only small amounts were detectable in primary monocytes. However, identical conditioned tumor SN induced the production of both cytokines in monocytes after cultivation in 100% conditioned media for 2 days. Mean values of three experiments are shown; samples were used in duplicates. The GHD-1 cancer cell line that does not produce PGE2 (Table 1) does not induce cytokine production (not shown).

TNF-{alpha} is a cytokine that has been described to be induced in monocytes stimulated with human cancer cells (34) . TNF-{alpha} mostly displays proinflammatory properties, but is also able to block T cell proliferation (28 , 35) . We again performed ELISA assays that demonstrated that conditioned Tu-SN not only induce IL-10 but also induce the production of TNF-{alpha} in monocytes (Fig. 1) .

Tumor supernatants down-regulate surface expression of CCR5
CCR5 is a chemokine receptor expressed on monocytes and certain T lymphocytes (24 , 36) . It has been identified as a coreceptor for HIV entry (25) , but its physiological role is activation and regulation of responses to chemokines. To investigate the influence of tumor cell SN on the surface expression of CCR5, we cultivated freshly isolated monocytes for 2 days in different conditioned tumor cell media and investigated CCR5 by FACS analysis. Vitality of monocytes was usually >90% and was not influenced by Tu-SN as tested by trypan blue exclusion. As demonstrated in Fig. 2A , the incubation with Tu-SN led to a significant down-regulation of CCR5 in comparison to incubation with cell culture medium. Supernatants from a tumor cell line that does not produce PGE2 (GHD-1) did not show this effect (data not shown). Most likely, this effect is mediated by PGE2 present in the tumor cell supernatants, since the observed effect can be inhibited by aspirin (Fig. 2B ) and indomethacin (not shown) and simulated with purified PGE2 (Fig. 2C ).



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  		Figure 2. Tumor-SN down-regulate the expression of CCR5 on monocytes. A) Incubation of monocytes for 2 days with FaDu-SN resulted in a clear down-regulation of CCR5 (black line) in contrast to cell culture medium (gray trace). This effect could be abolished, when FaDu cells had been grown in the presence of 1 mM aspirin (B) or 13 µM indomethacin (C). CCR5 was similarly down-regulated when purified 10-5 M PGE2 was added to cell culture medium (D).

Tu-SN reduce the chemotaxis of monocytes
Chemokines are produced locally in response to infections and immune reactions. The migration of immune cells in the direction of higher chemokine concentrations is necessary for efficient immune responses (21 , 37 , 38) . Since MIP-1ß, which is produced by activated T cells (21) , binds to CCR5, and Tu-SN down-regulate CCR5, we performed a chemotaxis assay in order to determine whether CCR5 down-regulation results in a reduced ability of primary monocytes to migrate in the direction of higher MIP-1ß concentrations. Therefore, primary monocytes were cultivated for 1 day in either FaDu-SN or cell culture medium. Migration was then performed against MIP-1ß (20 ng/ml) for 3 h through 8 µm pore filters. As pointed out in Fig. 3 , the pretreatment of monocytes with FaDu-SN significantly (P<0.003) reduces the number of migrated monocytes to ~50% compared with DMEM. Migration inhibition was partially abrogated by cultivation of FaDu cells in the presence of 1 mM aspirin.



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  		Figure 3. FaDu-derived factors interfere with the migration of monocytes. Isolated monocytes were cultivated for 1 day in either conditioned FaDu-SN or cell culture medium (DMEM). Transmigration of monocytes through 8 µm pore size filters was then performed against MIP-1ß (20 ng/ml) for 4 h. Cells that reached the lower chamber were stained with Giemsa black and counted under light microscopy. Migration was reduced to almost 50% after incubation in FaDu-SN and was much less inhibited, when FaDu-SN were generated in the presence of 1 mM aspirin (FaDu-SN + Asp). Results represent the mean of 4 values. P < 0:003 (paired Student‘s test). A representative result of three independent experiments is shown.

Tu-SN down-regulate adhesion molecules on monocytes and inhibit adhesion
As demonstrated in a recent study, the number of immune cells in the tumor infiltrate is increased after administration of indomethacin (39) . Since adhesion to the endothelium is another pivotal step for leukocytes in order to leave the bloodstream, we investigated whether Tu-SN also inhibit the function of the ß2-integrin Mac-1 on monocytes. We incubated monocytes for 2 days in either cell culture medium or conditioned tumor supernatants and investigated surface expression of Mac-1 by FACS. We found that both chains of Mac-1, CD11b and CD18, were clearly down-regulated after incubation in FaDu-SN (Fig. 4 ). This modulation was not observed when FaDu-SN were generated in the presence of aspirin or indomethacin (not shown).



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  		Figure 4. Down-regulation of Mac-1 expression after incubation of monocytes in FaDu-SN. Monocytes were incubated for 2 days with either FaDu-SN (black line) or cell culture medium (gray trace) and investigated for Mac-1 expression. Both chains of the molecule, CD11b and CD18, were clearly down-regulated after incubation in FaDu-SN in comparison to cell culture medium. Similar results were observed after addition of purified PGE2 to the medium. FaDu-SN generated in the presence of aspirin (1 mM) and Indomethacin (13 µM) did not show this effect (data not shown).

The main ligand for Mac-1 is ICAM-1 present on endothelial cells, and this interaction is pivotal for adhesion and extravasation of monocytes (40) . Therefore, we next investigated whether down-regulation of Mac-1 has consequences for the adhesion of monocytes to recombinant ICAM-1. To this end, cell culture dishes were coated with the fusion protein Fc/ICAM-1 and monocytes preincubated with FaDu-SN, which had been generated in the presence of 1 mM aspirin, purified PGE2, or cell culture medium medium only. It became clear that FaDu-SN and purified PGE2 strongly inhibited binding of monocytes to ICAM-1, whereas FaDu-SN that were generated in the presence of aspirin had a much less dramatic effect (Fig. 5A, B ).



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  		Figure 5. A, B) Incubation of monocytes with FaDu-SN reduces adhesion to endothelial cells and ICAM-1. Primary monocytes were precultivated with DMEM or FaDu-SN, labeled with CMFDA, and 2 x 104 cells/well were then added to ICAM-1-coated culture dishes. After 2 h at 37°C, the plate was washed intensively and fluorescence was counted using a Wallac 1420 multilabel counter at 525 nm. Adherent cells were calculated as % of input fluorescence. A representative of three experiments is shown. C) For binding of monocytes to endothelial cells, pretreated monocytes were added to a confluent monolayer of endothelial cells for 30 min. Adhesion of monocytes in DMEM was set to 100%.

In an additional set of experiments, we investigated whether tumor supernatants also interfere with the adhesion of monocytes to endothelial cells. We isolated human umbilical cord endothelial cells and monocytes and pretreated them with DMEM or FaDu-SN. Monocytes were then labeled with CMFDA and put onto the endothelial cell layer for 30 min. After intensive washings, adherent monocytes were counted with a fluorometer. As shown for recombinant ICAM-1, FaDu-SN also reduced the adhesion of monocytes to endothelial cells (Fig. 5C ).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Tumor immunity, i.e., the evasion of tumor cells from recognition and subsequent elimination through the immune system, is one of the most intensively investigated aspects of tumor etiology. To evade immune cell attacks, tumors have established escape mechanisms: they down-regulate MHC class I and II molecules to become ‘invisible’ to T lymphocytes, do not express costimulatory molecules necessary for proper T cell activation, and/or produce immunosuppressive factors that interfere with the activity of immune cells.

The development of malignant tumor cells is a multistep process explained mosly by genetic mutations and altered protein expression. Deregulation of lipid metabolism has been considered less often as a tumorigenic factor. Although the immunosuppressive effects of PGE2 have been known for several years (41) , cyclooxygenases and metabolites of arachidonic acid only recently gained the attention of oncologists. This may be attributed to clinical observations in cancer patients where the long-time application of aspirin and indomethacin have positive effects on tumor rate (4 , 42 , 43) . Along this line, animal models clearly demonstrated that chemokines and blockade of PGE2 synthesis improved the quality and quantity of the tumor infiltrate resulting in reduced tumor growth in vivo (44 45 46 47 48) .

Most effects of PGs are probably exerted through an elevation of intracellular cAMP levels. However, the exact mechanism of how PGs perform their immunosuppressive effects is not fully understood. Here, we demonstrate that tumor cell-derived PGE2 causes down-regulation of the chemokine receptor, CCR5, and the ß2-integrin, Mac-1, on monocytes (Table 2 ). As a consequence, the ability of these monocytes to adhere to the endothelial cells and migrate in the direction of higher concentrations of the chemoattractant MIP1ß is greatly reduced. Since both processes are pivotal for efficient tumor cell elimination, this may describe a new strategy of tumoral escape from immune responses. Impaired leukocyte migration due to PGE2-mediated down-regulation of CCR5 may also explain why administration of NSAIDs increases the number of immune cells in the tumor bed in patients with head and neck cancer (39) . Down-regulation of CCR5 and Mac-1 was not due to toxic factors in tumor cell supernatants, since viability and MHC class I and CD86 expression levels were not affected and CD80 was only marginally affected (not shown). In addition, tumor cells induce production of the immunomodulating cytokines IL-10 and TNF-{alpha} in monocytes, which may also contribute to inactivation of monocytes and probably other leukocyte subsets.


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  		Table 2. Effects of TNF-{alpha}, IL-10, and PGE2 on CD11b levels on primary monocytesa

In summary, we describe the down-regulation and partial loss of function of two PGE2 target molecules on monocytes (CCR5, Mac-1). These phenomena result in a reduced potential of monocytes to adhere to endothelial cells and migrate in the direction of the chemoattractant MIP-1ß. The significance of our observations is further supported by a report demonstrating enhanced tumor growth and reduced monocyte recruitment in an animal model after blocking Mac-1 or the chemokine MCP-1 (49) . In addition, tumor-derived PGE2 induces the production of IL-10, which is known to inhibit immune cell function (50 51 52) . Tumor-derived PGE2 also induces TNF-{alpha}, which has been described to inhibit T cell proliferation (28 , 35) and down-regulation of CCR2 on monocytes (53) . Since the number and composition of tumor infiltrating leukocytes are probably key parameters for the clinical prognosis of cancer patients (44 , 47 , 54) , our data may provide the first molecular explanation for the beneficial therapeutic effects of nonsteroid antiinflammatory drugs like aspirin and indomethacin in tumor patients.


   ACKNOWLEDGMENTS
 
We thank Dr. W. Hammerschmidt for critically reading this manuscript. This work was supported by the Rudolf-Bartling Stiftung and Institutional Grants.


   FOOTNOTES
 
2 Present address: Department of Otorhinolaryngolgy, Albert-Szent-Györgyi Medical University, H-6725 Szeged, Hungary.

Received for publication March 14, 1999. Revised for publication November 5, 1999.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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