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Published online before print December 4, 2003
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* Institute and Department of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan;
Dunn School of Pathology, University of Oxford, United Kingdom; and
Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan
1Correspondence: Institute of Microbiology and Immunology, National Yang-Ming University, Shih-Pai, Taipei 112, Taiwan. E-mail: slhsieh{at}ym.edu.tw
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: tumor necrosis factor • phagocytosis • apoptosis • inflammation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Macrophages are regarded as professional phagocytes, which engulf pathogens to initiate the innate-immune response and then in turn orchestrate the adaptive response [9 ]. In their capacity as innate-immune cells, macrophages express pattern-recognition molecules to recognize a broad range of pathogens through their common components, resulting in the transcriptional activation of a wide variety of inflammatory- and immune-response genes [10 ]. Conversely, macrophages also play an important role in the recognition and clearance of apoptotic cells [11 ]. Unlike the uptake of infectious agents that cause proinflammatory responses [12 ], phagocytosis of apoptotic cells results in anti-inflammatory responses [13 ]. Numerous studies have demonstrated that the immune function of macrophages is altered in cancer patients with solid tumors and that this is often associated with a poor prognosis [14 15 16 ]. Moreover, the functioning of tumor-associated macrophages (TAMs) is impaired [17 ], and these TAMs differ from normal macrophages, for example, by constitutively secreting reduced levels of interleukin (IL)-1 and TNF and producing substantial amounts of transforming growth factor-ß (TGF-ß) [18 ]. Therefore, we asked whether DcR3.Fc is able to modulate the biological functions of macrophages.
To address this question, an in vitro culture system was used to monitor the differentiation and activation of a CD14+ monocyte-derived macrophage under the influence of DcR3.Fc. Here, we report that DcR3.Fc suppresses the differentiation of CD14+ monocytes into macrophages. In addition to modulating the expression of several surface markers of macrophages, the phagocytic activity and the response to lipopolysaccharide (LPS) were severely impaired in a DcR3.Fc-treated CD14+ monocyte-derived macrophage (DcR3.Fc-treated M
). This observation further suggests that DcR3 may have diverse, suppressive effects on macrophage activation and supports the hypothesis that DcR3 acts as an immunosuppressive factor to down-regulate host immunity to the invasion of cancer cells and pathogens.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(hIFN-) was from Roche Diagnostics GmbH (Mannheim, Germany). LPS (Escherichia coli serotype O111:B4), nitroblue tetrazolium, PKH 67 Green Fluorescent Cell Linker Mini Kit, 5(6)-carboxytetramethyl-rhodamine N-hydroxy-succinimide ester [5(6)-TAMRA], green fluorescent latex beads, Wright stain solution, ovalbumin (OVA), anti-Flag® M2 affinity gel, and 
-naphthyl-acetate esterase (ANAE) staining kit were purchased from Sigma Chemical Co. (St. Louis, MO), and rabbit anti-OVA antiserum was from Cappel (Organon Teknika, Turnhout, Belgium). Anti-M-CSF receptor (M-CSFR) and anti-LIGHT polyclonal antibody were purchased from Upstate Biotechnology (Lake Placid, NY) and R&D Systems, respectively.
Generation of recombinant DcR3.Fc, DcR3.Flag, and DcR3.Fcmut fusion proteins
Recombinant DcR3.Fc fusion protein was produced as described previously [8
]. To generate DcR3.Flag, the open reading frame of the hDcR3 gene was isolated by reverse transcriptase-polymerase chain reaction (RT-PCR) using the forward primer, 5'-GGAATTCAAGGACCATGAGGGCGCTG-3', and the reverse primer, 5'-GGAATTCGTGCACAGGGAGGAAGCGC-3'. The amplified product was ligated into the EcoRI site of the CMV Tag4a (Stratagene, La Jolla, CA) vector containing the Flag Tag. The DcR3.Flag fusion gene was then subcloned into the pBacPAK9 vector (Clontech Laboratories) and cotransfected with linearized BacPAK6 DNA (Clontech Laboratories) into Sf21 cells. The supernatant from recombinant virus-infected Sf21 cells was filtered and purified on an anti-Flag® M2 affinity gel. The bound DcR3.Flag protein was then eluted with 0.1 M glycine buffer (pH 3.0) followed by dialysis against phosphate-buffered saline (PBS). To prevent the binding of DcR3.Fc recombinant protein to the hFc receptor, the mutated Fc fragment of human immunoglobulin G (hIgG)1 (L234A, L235E, G237A, and P331S) [19
] was used to replace the wild-type Fc to generate the recombinant DcR3.Fcmut fusion protein.
Culture of CD14+ monocyte-derived macrophages
Peripheral mononuclear cells were isolated from the blood of healthy donors by standard density gradient centrifugation with Ficoll-Paque (Amersham Biosciences, Piscataway, NJ). CD14+ cells were subsequently purified from peripheral mononuclear cells by high-gradient magnetic sorting using the VARIOMACS technique with anti-CD14 microbeads (Miltenyi Biotec GmbH, Bergisch Gladbach, Germany). CD14+ monocytes were cultured in complete RPMI-1640 medium (Life Technologies, Gaithersburg, MD) supplemented with 10 ng/ml hM-CSF in the presence or absence of hIgG1 or different receptor.Fc fusion proteins (Fas.Fc, LTßR.Fc, DR3.Fc, DcR3.Fc, and DcR3.Fcmut) for 6 days. Fresh medium supplemented with hM-CSF (10 ng/ml) in the presence or absence of hIgG1 or receptor.Fc was added on day 3.
Flow cytometry and antibodies
Flow cytometry was used to assess the expression of specific cellular surface markers on monocytes or macrophages. Before staining, cells were harvested and washed twice with fluorescein-activated cell sorter (FACS) staining/washing buffer [1% (v/v) fetal calf serum and 0.1% (v/v) NaN3 in PBS], followed by incubation with monoclonal antibody (mAb) directed against specific cell-surface markers. Stained cells were analyzed on a FACSCalibur system (Becton Dickinson, Mountain View, CA) using CellQuestTM software (Becton Dickinson). Reagents used for flow cytometry were as follows: Fluorescein isothiocyanate (FITC)-conjugated mAb against CD36 (clone CB38); phycoerythrin (PE)-conjugated mAb against CD11c (clone B-ly6) and CD16 (clone 3G8); and CyChrome-conjugated mAb against CD3 (clone HIT3a) were from BD Biosciences (San Diego, CA). The mAb against CD51/61 (clone 23C6) and CD206 (clone 15-2), FITC-conjugated mAb against human leukocyte antigen (HLA)-DR (clone B-F1), and PE-conjugated mAb against CD14 (clone UCHM1) were from Serotec (Oxford, UK), and the mAb against M-CSFR (clone 12-2D6) and CD68 (clone Ki-M7) were from Zymed (South San Francisco, CA)and Caltag Laboratories (Burlingame, CA), respectively. FITC-conjugated goat anti-mouse IgG was from Jackson ImmunoResearch Laboratories (West Grove, PA).
LPS stimulation and semiquantitative RT-PCR
Macrophages were presensitized with 200 U/ml IFN- for 2 h before addition of LPS (1 µg/ml) for 30 min. After LPS stimulation, total RNA was extracted using RNAzolTM B (Biotecx Laboratories, Houston, TX) according to the manufacturer’s instructions. First-strand cDNAs were transcribed from total RNA and served as templates in PCR reactions using the ProSTARTM first-strand RT-PCR kit (Stratagene, West Cedar Creek, TX). The sequences of PCR primers used are as follows: IL-1ß (sense, 5'-CCTGTGGCCTTGGGCCTCAA-3'; antisense, 5'-GGTGCTGATGTACCAGTTGGG-3'); IL-6 (sense, 5'-TCAATGAGGAGACTTGCCTG-3'; antisense, 5'-GATGAGTTGTCATGTCCTGC-3'); TNF- (sense, 5'-ACAAGCCTGTAGCCCATGTT-3'; antisense, 5'-AAAGTAGACCTGCCCAGACT-3'); inducible nitric oxide synthase (iNOS; sense, 5'-ACATTGATCAGAAGCTGTCCCAC-3'; antisense, 5'-CAAAGGCTGTGAGTCCTGCAC-3'); actin (sense, 5'-GACTACCTATGAAGATCCT-3'; antisense, 5'-CCACATCTGCTGGAAGGTGG-3'); FasL (sense, 5'-CAGCTCTTCCACCTACAGAAGG-3'; antisense, 5'-CTCTTAGAGCTTATATAAGCCG-3'); LIGHT (sense, 5'-AGATCTTGACGGACCTGCAGGCTCC-3'; antisense, 5'-CTTCACACCATGAAAGCCC-3'); TL1A (sense, 5'-ATGGCCGAGGATCTGGG-3'; antisense, 5'-GTCTTCCGACTCTGGGATCAG-3'); ß2µ (sense, 5'-CCAGCAGAGAATGGAAAGTC-3'; antisense, 5'-GATGCTTACATGTCTCG-3').
Staining with Wright stain, nitroblue tetrazolium (NBT), and ANAE
Macrophages were cytospun onto a glass slide at 300 rpm for 3 min using Cytospin 2 centrifuge (Shandon, Pittsburgh, PA), followed by staining with Wright stain for 1 min and observation under a light microscope. To determine the production of free radicals by macrophages, LPS-stimulated macrophages were incubated with freshly prepared NBT solution (0.4 mM) for 2 h at 37°C, followed by examination under a light microscope to observe the formation of blue formazan deposits. ANAE activity was detected using a commercial kit (Sigma Chemical Co.) according to the vendor’s instructions.
Preparation of immune complexes and apoptotic Jurkat cells
OVA/anti-OVA immune complexes (OVA-ICs) were formed by incubating 0.3 µg/ml OVA with 20 µg/ml rabbit anti-OVA antisera for 30 min at 37°C as described previously [20
]. Red fluorescent Jurkat cells were prepared by incubating 3 x 107 cells with 50 µg 5(6)-TAMRA as described previously [21
], and the labeling of Jurkat cells with green fluorescent PKH 67 was performed according to the supplier’s instructions. The fluorescent Jurkat cells were exposed to UV irradiation at 254 nm for 10 min and incubated for a further 2 h. More than 80% of Jurkat cells became apoptotic as indicated by Annexin V/propidium iodide double-staining.
Phagocytic assay
To observe the phagocytic activity of macrophages, CD14+ monocyte-derived macrophages (5x105) were cultured in glass-bottomed culture dishes (MatTek Corp., Ashland, MA), followed by incubation with OVA-ICs, green fluorescent latex beads (0.026%), or apoptotic Jurkat cells (5x106) at 37°C for 1 h (for OVA-ICs and apoptotic Jurkat cells) or for 2 h (for latex beads). After incubation, cells were washed with PBS three times, then incubated with fixation solution [4% (v/v) paraformadehyde/400 mM sucrose in PBS] at 25°C for 1 h, and then permeabilized with 0.1% (v/v) Triton X-100 in fixation solution for 15 min before incubation with 0.5% (w/v) bovine serum albumin in PBS for 1 h. To visualize OVA-ICs, cells were incubated with FITC-conjugated goat anti-rabbit IgG, and F-actin was detected by addition of rhodamine- or FITC-conjugated phalloidin (Molecular Probes, Eugene, OR) for 15 min at 25°C. Samples were examined using a TCS SP2 confocal microscope (Leica Microsystems, Heidelberg, Germany). To differentiate between apoptotic cells adsorbed onto thesurface and those engulfed by macrophages, a quantitative flow cytometric assay was used. A mixture of macrophages and apoptotic Jurkat cells was stained with CyChrome-conjugated anti-CD3 mAb, under conditions whereby only the apoptotic Jurkat cells adsorbed to macrophage surface but not the engulfed apoptotic cells could be detected [22
].
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Inhibitory effects of DcR3.Fc on the phagocytic activity of macrophages
One of the most important characteristics of macrophages is their ability to capture and internalize particles, including opsonized materials, infectious agents, senescent cells, and apoptotic cells [11
]. As DcR3.Fc down-regulated the expression of CD16 [Fc receptor for IgG (FcR)III; Fig. 1
] and CD64 (FcRI; data not shown), which are essential for the uptake of immune complexes [23
], we tested whether phagocytic activity to immune complexes (Fc receptor-mediated phagocytosis) and latex beads (nonspecific phagocytosis) was impaired in DcR3.Fc-treated M. Compared with hIgG1-treated M (Fig. 2A
, middle), DcR3.Fc-treated M (Fig. 2A
, left) lost the ability to take up OVA/anti-OVA-ICs to the same extent as that of cytochalasin B-treated M (Fig. 2A , right). In addition, DcR3.Fc-treated M also lost the ability to take up green fluorescent latex beads (Fig. 2C)
. The inhibitory effect of DcR3.Fc on the uptake of OVA-ICs and fluorescent latex beads was dose-dependent (Fig. 2B
and 2D)
. These observations demonstrated that DcR3.Fc did not only affect CD16 and CD64 expression but also suppressed phagocytic activity.
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for 1 h, and then examined by a confocal microscope or a flow cytometer. In DcR3.Fc-treated M, most of the apoptotic cells adhered to the macrophage outer membranes, and only a few cells were engulfed (Fig. 3A
, right). In contrast, almost all hIgG1-treated M contained apoptotic Jurkat cells inside the cytoplasm under the same conditions (Fig. 3A
, middle). To quantitate the uptake of apoptotic Jurkat cells by macrophages, PKH 67-labeled Jurkat cells were incubated with hIgG1- or DcR3.Fc-treated M for 1 h. To distinguish the apoptotic cells adhered to the outer surface of macrophages from those that have been engulfed, CyChrome-conjugated anti-CD3 mAb was used to detect Jurkat cells adherent to the cell surface. Therefore, PKH67-labeled adherent, apoptotic Jurkat cells would be detected by CyChrome-conjugated anti-CD3 mAb and become CyChrome+/PKH 67+, and those engulfed by macrophages would become CyChrome-/PKH 67+. In cytochalasin B-treated M, almost all the apoptotic cells were located outside macrophages (CD11c+/CyChrome+/PKH 67+) as expected (98%). In contrast, the majority of the apoptotic cells (76%) was engulfed by hIgG1-treated M and became CD11c+/CyChrome-/PKH 67+ (Fig. 3B
, upper). In contrast, in macrophages treated with DcR3.Fc (5 µg/ml), only 14% of apoptotic cells were engulfed. The inhibitory effect of DcR3.Fc on the uptake of apoptotic cells by macrophages was dose-dependent (Fig. 3B
, lower).
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vß3) [24
, 25
]. As CD14 has been shown to be down-regulated in DcR3.Fc-treated M (Fig. 1A)
, we wanted to determine whether the expression of CD36 (scavenger receptor B) and CD51/61 (vß3 vitronectin receptor), two other receptors involved in apoptotic cell uptake, were also suppressed in DcR3.Fc-treated M. As shown in Figure 3C
, the expression of CD36 was down-regulated by DcR3.Fc, and the expression of CD51/61 remained the same in hIgG1- and DcR3.Fc-treated M (Fig. 3C) . Therefore, the down-regulation of receptors involved in apoptosis by DcR3.Fc is selective.
Impaired responses to LPS in DcR3.Fc-treated monocyte-derived macrophages
In addition to its role to in the uptake of apoptotic cells, CD14 (better known as a LPS-binding protein receptor) is essential for an enhanced response to LPS. It has been shown that LPS, the major structural component of the outer wall of Gram-negative bacteria, is a potent stimulator of the inflammatory response via its interaction with CD14 and LPS-binding protein [26
]. As CD14 was down-regulated by DcR3.Fc, we were interested to know whether CD14 down-regulation on DcR3.Fc-treated M correlated with their response to LPS. In hIgG1-treated M, a 30-min incubation with LPS resulted in the increased expression of IL-1ß, IL-6, TNF-, and iNOS. In contrast, the expression of iNOS in DcR3.Fc-treated M was completely suppressed, and the expression of IL-1ß, IL-6, and TNF- was also partially suppressed (Fig. 4A
). The decreased expression of TNF- indicated by RT-PCR was confirmed by intracellular staining using anti-TNF- mAb (Fig. 4B)
. Compared with hIgG1-treated M, the secretion of TNF- in response to LPS stimulation (ranging from 1 to 1000 ng/ml) was impaired in DcR3.Fc-treated M (Fig. 4B)
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and iNOS are critical for free-radical generation in macrophages, the down-regulation of TNF- and iNOS should decrease the production of free radicals able to oxidize several substances, including the NBT, widely used for oxidative burst assays. To confirm the suppressive effect of DcR3.Fc on free-radical production, DcR3.Fc-treated M were incubated with NBT to test its ability to oxidize NBT after LPS stimulation. As shown in Figure 4C
, NBT was converted from reduced status (light yellow) to oxidized status (purple-blue) in hIgG1-treated M (Fig. 4C
, left), and NBT remained reduced (light yellow) in DcR3.Fc-treated M (Fig. 4C , right). This demonstrated that DcR3.Fc is able to down-regulate production of several inflammatory mediators secreted by macrophages in response to LPS.
DcR3.Fc down-regulates the expression of M-CSF receptor
It is known that M-CSF up-regulates the M-CSF receptor in CD14+ monocytes, and the differentiation of CD14+ monocyte into macrophages in the in vitro culture system relies on the M-CSFR-mediated signaling [27
28
29
30
]. The diverse, suppressive effects of DcR3.Fc raised the possibility that DcR3.Fc might interfere with the M-CSF-induced signaling by down-regulating M-CSFR expression. To test this hypothesis, a time-course study was performed to monitor the expression of M-CSFR by flow cytometry. In control cells, M-CSFR was up-regulated gradually in the M-CSF or M-CSF + hIgG groups (Fig. 5A
). In contrast, M-CSFR expression was down-regulated in the M-CSF + DcR3.Fc group. This observation was further confirmed by Western blot analysis (Fig. 5B)
. This suggests that DcR3.Fc-induced suppressive effects on macrophage might be attributed, at least partially, to its ability to down-regulate M-CSFR suppression.
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, and TL1A mRNA is constitutively expressed in freshly isolated monocytes and M-CSF-induced macrophages and is slightly up-regulated in DcR3.Fc-treated M. However, TL1A and LIGHT are not detectable in the culture supernatants or cell lysates by Western blot analysis (Fig. 6B
and 6C)
. As neither DR3.Fc nor LTßR.Fc and HVEM.Fc have any modulatory effect on the cell functions tested here (Fig. 1A)
, we conclude that the DcR3.Fc-mediated effect is not occurring via its interaction with FasL, LIGHT, and TL1A.
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1ß2), HVEM.Fc (receptor for LIGHT), Fas.Fc (receptor for FasL), and DR3.Fc (receptor for TL1A), the modulatory effects in this study are unique to DcR3.Fc (Fig. 1A)
. Although the Fc portions of all these receptor.Fc proteins are identical, we still cannot rule out the involvement of the Fc receptor in DcR3.Fc-mediated immunomodulation. To address this question, the Flag-tagged, recombinant DcR3.Flag as well as the DcR3.Fc mutant (DcR3.Fcmut, which lacks the ability to bind to Fc receptor and to activate complement) [19
] were generated to address this question. As shown in Figure 7A
, DcR3.Flag alone does not have any effect on the expression of CD14 and CD16, but cross-linking DcR3.Flag by anti-Flag antibody restores its modulatory effect to that of DcR3.Fc. The DcR3.Fcmut still maintains the ability to down-regulate the expression of CD14 and CD16, although its potency is less than wild-type DcR3.Fc. This suggests that the DcR3-mediated immunomodulation is cross-linking-dependent and that the Fc receptor might also be involved to potentiate the DcR3.Fc-mediated activity.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We have observed that its ability to bind the Fc receptor plays a role in DcR3.Fc-mediated immunomodualtion. However, as other receptor.Fc fusion proteins we tested, such as Fas.Fc (receptor for FasL), LTßR.Fc (receptor for LIGHT and LT1ß2), DR3.Fc (receptor for TL1A), and HVEM.Fc (receptor for LIGHT), do not have similar activities to DcR3.Fc, we propose that the unique activity of DcR3.Fc among these recombinant receptor.Fc fusion proteins cannot be simply attributed to its binding to the Fc receptor. One possibility is that DcR3.Fc binds to an Fc receptor on one cell, and the DcR3 portion binds to ligand on another cell. This will induce cell aggregation and increase cross-linking activity. However, all the macrophages observed were in single-cell morphology after the addition of DcR3.Fc. An alternative is that dimeric DcR3.Fc cross-links an as-yet unidentified ligand on target cells (Fig. 7B
, left) to trigger a signaling cascade. The reduced potency of DcR3.Fcmut might be a result of the following reasons: Binding to Fc can increase the stability and cross-linking abilities of wild-type DcR3.Fc, or DcR3.Fcmut contains only one disulfide bond, as compared with two disulfide bonds in wild-type DcR3.Fc, hence its cross-linking ability is weaker than wild-type DcR3.Fc.
Among the receptor.Fc fusion proteins, it is surprising to find that DcR3.Fc has such diverse effects in modulating the differentiation and activation of DCs [8 ] and macrophages. As DcR3.Fc can skew T cell differentiation to a Th2-predominant phenotype [8 ], as well as down-regulating the production of prolinflammatory cytokines and free radicals (Fig. 4) , DcR3.Fc might have the potential to become an immunosuppressant for the treatment of certain autoimmune diseases in the future.
As FasL, LIGHT, and TL1A were undetectable in monocytes by flow cytometry staining [3 , 8 ] or by Western blot analysis (Fig. 6) , and the DcR3-induced modulatory effect is cross-linking-dependent, we suggest that DcR3 might modulate cell function via cross-linking an as-yet unidentified membrane protein of monocytes and macrophages. In our preliminary study, we have isolated several proteins migrating at 100, 66, and 50 kDa by DcR3.Fc affinity columns (unpublished), and the nature of these proteins is currently under investigation.
Numerous studies have demonstrated that immune function is affected in patients with solid tumors and that such effects are often associated with a poor prognosis [16 , 17 ]. Macrophages have been shown to aggregate in tumors, and macrophages residing within tumor masses, the so-called TAMs, act differently from activated, cytotoxic macrophages. For instance, TAMs isolated from breast, lung, and ovarian carcinomas constitutively secrete less IL-1 and TNF than do circulating monocytes and also produce substantial amounts of TGF-ß, a well-known suppressor of macrophage function [18 ]. Although Flag-tagged DcR3 depends on cross-linking by anti-Flag antibody to execute its modulatory effect, we cannot rule out the possibility that endogenous DcR3 might form stable dimers with repeating heparin disaccharides, similar to fibroblast growth factor-heparin complexes [31 , 32 ], thereby increasing its cross-linking ability in vivo. Transgenic mice overexpressing DcR3 should allow us to test this hypothesis.
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ACKNOWLEDGEMENTS |
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Received September 29, 2003; accepted November 10, 2003.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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