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B Signaling Pathway1
* Institute of Hygiene and Social Medicine, Leopold-Franzens University and Ludwig Boltzmann Institute for AIDS Research, Innsbruck, Austria;
Laboratory of Immunotherapy, Department of Otorhinolaryngology and
Central Institute for Blood Transfusion and Division for Immunology, University Hospital, Innsbruck, Austria;
Department of Dermatology and
¶ Institute of Pathophysiology, Medical School, University of Innsbruck, Innsbruck, Austria; and
|| Department of Immunology, Eötvös Loránd University, Budapest, Hungary
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Abstract |
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R-type II (CD32) with immobilized IgG (imIgG) can induce maturation of human monocyte-derived DC via the NF-
B signaling pathway. IgG-mediated maturation was accompanied by a moderate increase of IL-10 secretion, whereas no IL-12 production was observed. Involvement of CD32 was further supported by experiments with the anti-CD32 mAb, which blocked IgG-triggered DC maturation and cytokine secretion significantly. Furthermore, DC cultivated in the presence of imIgG induced allogeneic T cell proliferation. Because this imIgG-induced maturation was considerably impaired in monocyte-derived DC from systemic lupus erythematosus patients, we suggest that DC, which matured in the presence of immune complexes, may contribute to prevention of pathological immune responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent data indicate that LPS-induced maturation and activation of mouse DC is an NF-B-dependent process (6). It has been described that p65, c-Rel, and p50 were translocated early, whereas RelB was translocated later during activation of the mouse DC line D1 in the presence of LPS or Salmonella typhimurium (7). In humans, the expression of HLA class II and costimulatory molecules like CD80, CD86, and CD40 on monocyte-derived DC (MDC) can be down-regulated by blocking NF-B translocation to the nucleus (8). Furthermore, NF-B blockade down-regulates the secretion of the immunostimulatory cytokines IL-12 and TNF-
(8). Thus, various NF-B molecules may play a crucial role in DC-mediated immune responses.
Immature DC internalize pathogens or their products by several mechanisms including actin-dependent phagocytosis, macropinocytosis, and receptor-mediated endocytosis (9). Receptor-mediated endocytosis is a main mechanism of Ag uptake and may have profound effects on the outcome of the Ag presentation process by DC. DC have been reported to use FcR, which evolved to bind the Fc fragment of IgG for uptake of Ag opsonized with specific Ab (10, 11). Recently, it has been shown that murine DC express FcRI, FcRIIb1, FcRIIb2, and FcRIII (CD16) receptors (12). It has been described that the internalization of Ag-IgG complexes via FcR enhanced Ag presentation 100-fold compared with noncomplexed Ag (13). Human blood DC also express different types of FcRs, including FcRI (CD64) and FcRII (CD32) (14, 15). However, little is known about the effects of IgG or immune complexes on the maturation of human DC.
Formation and deposition of anti-DNA autoantibodies and immune complexes were shown to be pathogenic in systemic lupus erythematosus (SLE) (16). The development of disease has been shown to be associated with numerous environmental and genetic factors, including complement deficiencies, polymorphisms of cytokine or HLA genes as well as FcR alleles (17, 18, 19, 20). Furthermore, phenotypical and functional deficiencies of DC in SLE patients have been described (21, 22).
Therefore, we examined the role of FcR regarding the maturation process of human MDC. We have found that cross-linking of CD32 with human IgG can trigger maturation of DC via the NF-B signaling pathway. The IgG-mediated maturation was accompanied by the lack of IL-12 production and a modest increase of IL-10 secretion. Functional assays have shown that DC cultivated in the presence of immobilized IgG (imIgG) had a strong capacity to induce allogeneic T cell proliferation. MDC from SLE patients, cultivated on imIgG have shown considerably impaired maturation capability. These findings suggest that immune complexes might be involved in the regulation of DC maturation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Purified recombinant human IL-4 was obtained from PromoCell (Heidelberg, Germany). GM-CSF (Leucomax) and human IgG (Sandoglobulin) were purchased from Novartis (Vienna, Austria). LPS (Escherichia coli serotype 026:B6) was purchased from Sigma-Aldrich (St. Louis, MO). mAbs directed against cell surface markers (mouse anti-human CD1a, CD83, CD86, mannose receptor (MR), HLA class I, HLA class II, CD16, CD32, CD64, CD40, CD54, CD14) were obtained from BD PharMingen (San Diego, CA). FITC-conjugated goat anti-mouse Ig polyclonal Ab (pAb) was purchased from DAKO (Glostrup, Denmark). FITC-conjugated mAb directed against MR, CD83, CD86, and isotype controls were obtained from BD PharMingen (San Diego, CA). NF-B p65 and c-Rel mAb were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). In blocking experiments, FcRII-specific mAb AT10 (Serotec, Oxford, U.K.) and 7.30 (NeoMarkers, Fremont, CA) were used.
Patients and controls
Nine randomly selected patients suffering from SLE, which fulfill four or more of the American Rheumatism Association criteria were included. Patients were informed and gave their written consents to the experiments. The clinical and serologic features of SLE patients are summarized (Table I). Eighteen healthy volunteers served as the reference population.
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Peripheral blood was obtained from normal healthy donors at the local blood bank and from SLE patients in the Department of Dermatology (University of Innsbruck, Innsbruck, Austria). PBMC were isolated by centrifugation on a Ficoll-Hypaque (Pharmacia, Uppsala, Sweden) density gradient. Monocytes were separated from PBMC by adherence on gelatin-coated Petri dishes (23). Briefly, Petri dishes were coated with 2% gelatin for 2 h and preincubated at 37°C for 1 h with autologous serum before use. After 40 min of adherence at 37°C, nonadherent cells were removed by aspiration, and dishes were washed with warm RPMI 1640 medium (Life Technologies, Rockville, MD). Adherent cells were detached using medium supplemented with 5 mM EDTA. Monocytes were washed and cultivated in RPMI 1640/10% FCS supplemented with 1500 U/ml IL-4 and 1600 U/ml GM-CSF at a density of 106 cell/ml in six-well plates (Costar, Cambridge, MA) to prepare MDC. IL-4 (1000 U/ml) and GM-CSF (1600 U/ml) were added after 2 days. On day 5, cells were collected, washed, and transferred to a new plate. Cells were cultivated further for 2 days in the presence of fresh RPMI 1640/10% FCS medium supplemented with 1000 U/ml IL-4 and 1600 U/ml GM-CSF without any stimulation as immature DC (imDC) or in the presence of 100 ng/ml LPS to obtain mature DC (maDC). To investigate the effects of IgG on maturation, DC were incubated for 2 days in the presence of either soluble IgG, or on plates that were coated overnight with different concentrations of IgG (imIgG).
Flow cytometry
DC were washed twice in PBS supplemented with 1% BSA containing 0.01% sodium azide. Isotype control (IgG1-producing 1B7.11 cell line was obtained from American Type Culture Collection, Manassas, VA) or cell surface-specific mAb were added in a concentration of 5 µg/ml for 45 min at 4°C. Thereafter, cells were washed two times and incubated for 30 min with FITC-conjugated goat anti-mouse Ig pAb at 4°C. After washing, cells were resuspended and fixed in PBS/1% paraformaldehyde. The analysis was performed using a FACScan flow cytometer (BD Biosciences, Mountain View, CA) and CellQuest software (BD Biosciences).
MLR assay
MLR was performed by cocultivation of formaldehyde (4% in PBS) fixed DC at various dilutions with allogeneic T cells (range from 1/10 to 1/7290). After 5 days, cultures were pulsed with 1 µCi/well tritiated thymidine up to 20 h. Thereafter, cells were harvested and the radioactivity was measured using a beta counter (Canberra Industries, Meriden, CT).
Measurement of IL-10 and IL-12 p70 by ELISA
Supernatants of DC were collected at 24 and 48 h after stimulation and stored at -70°C until measurement. IL-10 and IL-12 p70 amounts were measured in culture supernatants from various experiments in duplicate by cytokine-specific, sandwich ELISA kits (R&D Systems, Minneapolis, MN) according to manufacturer’s instructions.
Immunocytochemistry
DC were cultivated in glass LabTek chambers (Nalge Nunc International, Naperville, IL) with different activation stimuli for 1, 2, 4, 6, and 24 h. Thereafter, cells were fixed overnight with PBS containing 4% paraformaldehyde and then permeabilized for 30 min in PBS/1% BSA/0.1% saponin. Cells were stained with mouse mAbs directed against human NF-B c-Rel and p65 at a 5 µg/ml concentration in PBS/1% BSA/0.1% saponin. After washing, cells were stained with tetramethylrhodamine isothiocyanate-conjugated rabbit anti-mouse IgG pAb (DAKO) and FITC-conjugated mouse anti-human HLA-DQ, DP, DR mAb (DAKO).
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Results |
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RII but not FcRI or FcRIII
Because DC express several FcRs dependent on their lineage and origin, the surface expression of these receptors was investigated on MDC. Monocyte-derived imDC on day 5 expressed CD32 (FcRII), but not CD16 (FcRIII) or CD64 (FcRI) (Fig. 1A), whereas monocytes expressed all three FcRs (data not shown). After 7 days of cultivation, DC expressed considerably lower amounts of CD32 (Fig. 1B). Similarly, we observed the same decrease of CD32 expression when DC were incubated in the presence of LPS (Fig. 1B). Upon cultivation in the presence of IgG, FcRII expression was not detectable (Fig. 1B).
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In initial experiments, the effects of IgG on expression of DC maturation markers were investigated. The surface expression of MR, CD83, and CD86 were determined by flow cytometry. Five-day-old imDC were cultivated for the next 2 days either in the presence of 100 µg/ml IgG in fluid phase (Fig. 2B), or on plates coated with IgG at concentrations of 10 and 100 µg/ml IgG (Fig. 2A), respectively. The effect of imIgG on DC maturation was compared either with nonstimulated imDC or with LPS-stimulated maDC (Fig. 2A). High expression of CD83 and CD86 together with low expression of MR on the surface of DC indicated that DC have undergone a maturation process upon cultivation on plates coated with IgG. FACS analysis revealed that dependent on the donor, up to 90% of the DC reached a mature state after 2 days of cultivation in the presence of imIgG. Moreover, IgG-primed maturation of DC was dose-dependent. Cross-linking of FcRs was necessary for initiation of this process, because no maturation in the presence of soluble monomeric IgG was observed (Fig. 2B).
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RII-specific mAb AT10. The blockade of FcRII with 10 µg/ml AT10 completely inhibited the maturation of DC cultivated on IgG-coated plates (Fig. 3), whereas AT10 did not affect the surface expression of maturation markers on imDC (Fig. 3) or on LPS-stimulated DC (data not shown). Furthermore, the nonblocking anti-CD32 mAb 7.30 had no effect on DC maturation (data not shown).
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In additional experiments, we measured the surface expression of CD1a, HLA class I, HLA class II, CD40 and CD54, which are believed to be important for Ag-presentation by DC. Upon cultivation in the presence of different concentrations of IgG, the expression pattern was similar to LPS-treated DC. Moreover, when DC cultivated in the presence of imIgG were compared with LPS-treated DC, no significant difference in the expression of the above-mentioned cell surface markers could be detected (Table II).
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The ability of DC to stimulate allogeneic T cell proliferation has been investigated using a MLR assay. To exclude maturation of DC by allogeneic T cells during the MLR assay, formaldehyde-fixed cells were used. DC cultivated on plates coated with IgG at a concentration of 10 µg/ml, showed an increased activation of T cell proliferation (data not shown). In the case of DC, which were incubated in the presence of 100 µg/ml imIgG (Fig. 4A), we detected significant stimulatory potential on T cells compared with imDC (Fig. 4A). Of note, the stimulatory capacity of DC without formaldehyde fixation was similar to fixed cells, although the cpm values were two to three times higher (data are not shown). The stimulatory capacity of IgG on T cells was markedly inhibited by the addition of 10 µg/ml CD32-blocking mAb AT10 (Fig. 4B).
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B p65 and c-Rel to the nucleus
To analyze the stimulatory effect of imIgG on DC maturation, we investigated the translocation of nuclear factors p65 and c-Rel during maturation of DC. These NF-B molecules are activated in early stages of maturation and Ag presentation of mouse DC (8). The p65 and c-Rel molecules were translocated to the nucleus already at 1 h after stimulation in the presence of LPS. Similarly, we observed the same kinetics of NF-B translocation after cultivation of DC on slides coated with 100 µg/ml IgG (Fig. 5, red fluorescence). After 24 h of stimulation, HLA class II molecules were up-regulated on the surface of DC stimulated with LPS or IgG (Fig. 5, green staining).
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Because IL-10 and IL-12 play a key role in the regulation of the T cell response, we measured the secretion of these two cytokines in supernatants from cells incubated on IgG-coated plates during the 24-h cultivation period using cytokine-specific ELISA. Both IL-12 and IL-10 secretion were increased in the case of stimulation with 100 ng/ml LPS (Fig. 6, A and B). imIgG were not able to induce IL-12 production by DC (Fig. 6A). In contrast, a 2-fold increase in the amount of IL-10 secreted by DC upon cultivation with 100 µg/ml imIgG was detected, when compared with nonstimulated cells (Fig. 6B). The secretion of IL-10 from DC treated with 100 µg/ml imIgG was significantly blocked with 10 µg/ml AT10 mAb (Fig. 6C). The effect of an additional LPS dose on the cytokine secretion of DC was also investigated. For this, 5-day-old DC were cultivated either in the presence of 100 ng/ml LPS or different concentrations of imIgG for 2 days. As control cells, imDC were used. After these 2 days, all cells (LPS- and imIgG-induced DC as well as immature control DC) were restimulated with 100 ng/ml LPS and cytokines were measured after 24 h. LPS-induced DC were not able to respond to a secondary LPS boost, whereas immature control DC preserved the ability to answer to the LPS stimulus (Fig. 7). In case of 10 µg/ml imIgG, DC produced reduced amounts of the cytokines in response to the secondary LPS stimulus when compared with the immature control cells (Fig. 7). Similar to maDC, no cytokine production was observed, when DC, which were cultivated in the presence of 100 µg/ml imIgG, were restimulated with LPS (Fig. 7). To further analyze the effects of imIgG on cytokine production of DC, titration curves for both LPS and imIgG were done. LPS at low concentrations had the same effects on DC regarding expression levels of surface maturation markers and secretion of the cytokines IL-10 and IL-12 as imIgG-induced DC (Fig. 8).
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Finally, we investigated the effects of imIgG on the maturation of MDC obtained from nine SLE patients at different stages of the disease (Table I.). In the immature state, no significant difference in CD83 expression between control DC and DC from SLE patients was observed (Fig. 9A). After 48 h of cultivation in the presence of 100 µg/ml imIgG, significantly lower amounts of CD83+ cells were found in the case of MDC from SLE patients, when compared with IgG-stimulated DC from healthy donors (Fig. 9B). The decreased amounts of CD83+ cells from SLE patients (Fig. 9B) were comparable with the amounts of CD83+ cells from immature DC (Fig. 9A). No correlation between the disease activity (SLE disease activity index) and the impaired maturation of DC was found (data not shown). Compared with DC from healthy donors, only a slight reduction of CD83+ DC from SLE patients was observed in the presence of 100 ng/ml LPS (Fig. 9C). The impaired maturation of DC was not caused by a change of FcR surface density because there was no difference between the surface expression of CD16, CD32, or CD64 neither on DC at the time of IgG treatment nor on fresh isolated monocytes from both SLE patients and healthy donors (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R on the maturation of DC. To exclude the interference of complement or possible endotoxin contamination in IC preparations and to guarantee the reproducibility of results, imIgG was used in our experiments instead of IC.
First, we studied the expression of FcRI (CD64), FcRII (CD32), and FcRIII (CD16) on the surface of MDC. Human blood DC have been described to express FcRI and FcRII, whereas mouse DC express all FcRs: FcRI, RII, and RIII (13, 14, 15). The expression of FcRI on a subset of blood-derived DC has been observed (24), whereas other groups could not detect this surface protein (25). Because the level of FcRI expression on monocytes can be reduced by IL-4 (26), it was suggested that FcRI expression is down-regulated on MDC due to the presence of this cytokine during the culture (15). In accordance with these findings, 5-day-old immature MDC, which developed in the presence of GM-CSF and IL-4, expressed only FcRII (27, 28).
In the present study, we demonstrate that imIgG can induce the maturation of human MDC. This imIgG-induced mature phenotype of DC was reflected on the level of surface maturation markers, induction of the NF-B signaling pathway, T cell stimulatory capacity, and unresponsiveness to secondary stimuli. In accordance with current knowledge, DC can be divided into a tolerogenic immature and an immunogenic mature stage. However, recent findings change this model. A so-called semi-mature phenotype was described recently, which is characterized by a mature surface phenotype and T cell stimulatory potential together with the absence of proinflammatory cytokine secretion (29, 30). These semi-mature DC are believed to induce tolerance. Furthermore, IL-10-producing DC with mature phenotypes were shown to induce peripheral tolerance after respiratory exposure to Ag (31). This growing evidence proposes that although imIgG-induced DC show mature phenotypes, they might be rather tolerogenic than immunogenic due to their lack of IL-12 secretion and increased IL-10 production. In this manuscript we use the "mature" term in this context in the case of imIgG-induced maturation. Because MDC expressed only FcRII, we proposed that this receptor is involved in the imIgG-induced maturation process of DC. In a series of inhibitory experiments, we confirmed that only the FcRII-specific blocking mAb AT10 was able to reverse the stimulatory effect of cross-linked IgG on DC maturation. Thus, these data implicate that the cross-linking of FcRII with human IgG triggered the maturation of MDC.
It has been shown that IgG-mediated maturation of mouse DC depends on the -chain of FcRI and FcRIII (12). The participation of the -chain in the maturation process of mouse DC implied that an immunoreceptor tyrosine-based activation motif (ITAM)-bearing receptor might be involved in the maturation of human DC. Moreover, FcR-driven maturation of human MDC has been shown to be -chain-dependent (32). As human MDC do not express FcRI and RIII, we propose that the ITAM-containing an FcRIIa isoform may be responsible for the observed maturation of human DC. In addition, human macrophages express an immunoreceptor tyrosine-based inhibitory motif-containing FcRIIb, which can inhibit activation after coligation with ITAM-containing FcRs. Similarly to macrophages, it is possible that human MDC also express FcRIIb, thereby modulating the DC maturation. Furthermore, FcRII is a member of low affinity FcRs, which does not bind to monomer IgG with measurable affinity (11). The fact that monomeric, soluble IgG had no effect on human MDC corresponds with the necessity of the FcR cross-linking in the maturation process. Thus, different FcR-dependent signaling pathways seem to be involved in the maturation and activation processes of human and mouse DC, respectively. This is further supported by the fact that the genetic equivalent of human FcRIIa, carrying an ITAM, has not been found in the mouse (33).
In this study, DC cultivated in the presence of imIgG up-regulated the costimulatory molecules CD86 and CD83. No significant differences in the expression of other DC markers that are involved in Ag presentation such as CD1a, HLA class I, HLA class II, CD40, and CD54 were found. However, these DC were able to induce allogeneic T cell proliferation in the MLR assay. Our findings imply that the induction of T cell proliferation depends on the higher density of the costimulatory molecules on DC surface, rather than on expression of the above-mentioned molecules.
NF-B transcription factors are activated by different signaling pathways involved in immune function and development, such as T and B cell activation, regulation of immune homeostasis, cell differentiation, and Ag presentation (34). It has been shown recently that the extracellular signal-regulated kinase regulates the survival of DC, whereas NF-B is responsible for the maturation of LPS-activated DC (6). Furthermore, a role of NF-B in the effective Ag presentation has been implicated through the necessity of these transcription factors in the initiation of HLA class II, CD80, CD86, and CD40 up-regulation, as well as in IL-12 and TNF- production (7). NF-B p65, c-Rel, and p50 are translocated early, whereas RelB signaling occurs later after activation of DC with LPS or S. typhimurium (8). We observed similar kinetics of the NF-B p65 and c-Rel translocation, when MDC were incubated in the presence of cross-linked IgG. These findings demonstrate that IgG trigger DC maturation through a similar signaling mechanism as LPS-induced DC maturation. However, differences in IL-12 secretion in response to LPS and to imIgG indicate that alternative activation of NF-B subunits may be involved, because this cytokine was previously described to be down-regulated when NF-B translocation was blocked (7). These findings suggest that various members of the NF-B family may mediate distinct effects on DC function.
Activated myeloid DC have been described as the most potent producers of IL-12 that induce a Th1 response in activated T cells (35), whereas lymphoid DC derived from CD4+CD3-CD11c- cells have been defined by lack of IL-12 secretion and by induction of Th2 response (36). In addition, the CD1a- monocyte-derived DC subset, characterized by lack of IL-12 secretion and a Th2 cytokine pattern, has been identified recently (37). These studies indicate the existence of high and low IL-12-producing DC subsets, which polarize DC toward Th1 or Th2 response dependent on origin and culture conditions. When DC matured in the presence of imIgG, they were not able to secrete detectable amounts of IL-12. The decreased production of IL-12 was already observed in human monocytes stimulated with immune complexes (38). Furthermore, we detected a moderate increase of IL-10 secretion by imIgG-induced DC. The same increase of IL-10 production was observed in cultures of MDC upon cross-linking of FcR with IgA complexes (32). Based on the lack of IL-12 production and increased IL-10 secretion of DC in the presence of imIgG, we suppose that MDC might have the ability to differentiate to a Th2-inducing DC subset. Interestingly, low concentrations of LPS caused the same effect on DC as imIgG, which suggests the importance of the intensity of the stimulation on the maturation process of DC. These results suggest that suboptimal activation stimuli such as low concentrations of LPS or imIgG induce only partial maturation of DC, which is characterized by lack or decrease of cytokine production and therefore affect the outcome of the immune response.
Because evidence is provided that DC functions in SLE are altered (21, 22), we investigated the IgG-triggered DC maturation in the case of MDC from SLE patients. SLE is known as a complex autoimmune disease with a disturbance of both Th1 and Th2 response, which leads to activation of autoreactive T and B cell clones, respectively (39). The MDC from SLE patients, cultivated in the presence of imIgG, showed significant decreased amounts of CD83+ cells, when compared with healthy donors. The impaired maturation of IgG-triggered DC in an autoimmune disease suggests that these DC do not participate in induction of Th2 cells but they may be involved in a possible negative regulation of the immune response. An effect of corticosteroid (CS) treatment of SLE patients, which may affect DC function (40, 41, 42), can be excluded, because CS have a short biological half-life of 12–36 h (43). Therefore, we suppose that CS therapy might have only a marginal effect on maturation of MDC obtained from SLE patients after a 7-day cultivation in the absence of CS in cell culture.
The mechanism of negative regulation by IgG-triggered DC can be mediated by DC or by the activation of a regulatory T (TR) cell population. IL-10 seems to play a crucial role not only in function of TR cells but also in their generation. Phenotypically mature pulmonary DC, producing IL-10, may play a critical role in the induction of CD4+ T cell unresponsiveness after respiratory exposure to Ag (31). Adoptive transfer of pulmonary DCs from IL-10+/+, but not IL-10-/-, mice, induced Ag-specific unresponsiveness in recipient mice. Furthermore, the elevated IFN- level in SLE patients seems to be pathogenic, through its stimulatory effect on T and B cells, thereby triggering harmful immune response (44). The IFN-inducing factor in SLE was determined as small DNA-anti-DNA Ab or RNA-protein-autoantibody immune complexes (45). IFN- derives from natural IFN-producing cells, also called plasmacytoid DC precursors or pDC2, which are accumulated in inflamed lymph nodes of SLE patients (46, 47). IL-10, originated from monocytes, was able to inhibit IFN- production of DC2 in the transwell experiments (48). The amounts of IL-10, which blocked IFN- production in DC2, were comparable with the IL-10 secretion of IgG-triggered MDC. Therefore, we suggest that IL-10-producing DC, which developed in the presence of cross-linked IgG, might be involved in the generation of the TR cell population. Such mechanisms may limit the development of harmful T cell clones during immune activation, thereby preventing pathological responses to self-Ags.
Our findings reveal a new insight in the regulation of immune responses through interference of ICs with the maturation of DC.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Zoltán Bánki, Institut für Hygiene und Sozialmedizin, Leopold-Franzens-Universität, Fritz-Pregl Strasse 3, 6020 Innsbruck, Austria. E-mail address: Zolta.Banki{at}uibk.ac.at
3 Abbreviations used in this paper: DC, dendritic cell; MDC, monocyte-derived dendritic cell; SLE, systemic lupus erythematosus; imIgG, immobilized IgG; MR, mannose receptor; pAb, polyclonal Ab; imDC, immature DC; maDC, mature DC; IC, immune complex; ITAM, immunoreceptor tyrosine-based activation motif; CS, corticosteroid; TR, regulatory T cell.
Received for publication June 12, 2002. Accepted for publication February 4, 2003.
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 N. Fernandez, M. Renedo, S. Alonso, and M. S. Crespo Release of Arachidonic Acid by Stimulation of Opsonic Receptors in Human Monocytes: THE Fc{gamma}R AND THE COMPLEMENT RECEPTOR 3 PATHWAYS J. Biol. Chem., December 26, 2003; 278(52): 52179 - 52187. [Abstract] [Full Text] [PDF]
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J. Xie, J. Qian, S. Wang, M. E. Freeman III, J. Epstein, and Q. Yi Novel and Detrimental Effects of Lipopolysaccharide on In Vitro Generation of Immature Dendritic Cells: Involvement of Mitogen-Activated Protein Kinase p38< |
), when compared with DC from healthy donors (
). Five-day-old MDC were cultivated an additional 48 h in the presence of IL-4/GM-CSF medium alone (A), 100 ng/ml LPS (C) or were cultivated on plates coated with 100 µg/ml (B). The percent of CD83+ MDC obtained from 9 SLE patients and 18 controls is shown.