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, and Anti-Inflammatory Agents1
*
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, and
Servicio de Inmuno-oncología and
Servicio de Inmunología, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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,
IFN-
, and TGF-
were identified as negative regulators of DC-SIGN
expression, as they prevented the IL-4-dependent induction of DC-SIGN
mRNA on monocytes, and a similar inhibitory effect was exerted by
dexamethasone, an inhibitor of the monocyte-MDDC differentiation
pathway. The relevance of the inhibitory action of dexamethasone, IFN,
and TGF- on DC-SIGN expression was emphasized by their ability to
inhibit the DC-SIGN-dependent HIV-1 binding to differentiating MDDC.
These results demonstrate that DC-SIGN, considered as a MDDC
differentiation marker, is a molecule specifically expressed on
IL-4-treated monocytes, and whose expression is subjected to a tight
regulation by numerous cytokines and growth factors. This feature might
help in the development of strategies to modulate the DC-SIGN-dependent
cell surface attachment of HIV for therapeutic
purposes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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leads to
the appearance of MDDC with all the morphological, phenotypic, and
functional characteristics of mature DC (6, 7). DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN; CD209) is a type II membrane protein with a C-type lectin extracellular domain (10, 11). DC-SIGN plays an important role in establishing the initial contact between DC and resting T lymphocytes through its recognition of ICAM-3 (11), and it also mediates DC trafficking through interactions with endothelial ICAM-2 (12). Therefore, DC-SIGN appears to be a critical mediator of the migratory and T cell-interacting capabilities exhibited by maturing MDDC. In addition, DC-SIGN, originally described as a molecule with HIV gp120-binding ability (10), is now believed to capture HIV in the periphery and promote efficient infection in trans of cells expressing HIV receptors and coreceptors (13, 14, 15).
Given the relevance of the functional activities displayed by DC-SIGN
(16), determination of the signaling pathways and factors
controlling its expression might provide clues for modulating the
effector functions of DC in the initiation of immune responses.
Immunofluorescence analysis has revealed that DC-SIGN is only expressed
on a small percentage of CD14+ blood cells, while
it is highly expressed on immature DC in peripheral tissues and in
vitro derived MDDC (11, 12). By contrast, DC-SIGN mRNA has
been detected in PHA-activated PBL by means of RT-PCR analysis, an
approach which has also demonstrated the existence of an extensive
repertoire of DC-SIGN isoforms (17). To systematically
analyze the regulation of DC-SIGN expression during MDDC
differentiation, we have generated a DC-SIGN-specific mAb that allowed
the identification of DC-SIGN as an IL-4-inducible molecule and its
negative regulation by TGF- and type I and II IFN.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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GM-CSF (Leucomax) was purchased from Schering-Plough
(Kenilworth, NJ) and used at 1000 U/ml. M-CSF was a gift from Dr. E.
Fernández (Hospital de la Princesa, Madrid, Spain) and used at 25
ng/ml. IL-4 was obtained from PeproTech (Rocky Hill, NJ) and, unless
otherwise indicated, used at 1000 U/ml. IFN- and TGF- were from
R&D Systems (Abingdon, U.K.) and used at 500 U/ml and 10 ng/ml,
respectively. IFN- (Intron A IFN-2b; Schering-Plough) was
routinely used at 1000 U/ml. Dexamethasone was generously provided by
Dr. P. Aller (Centro de Investigaciones Biológicas, Madrid,
Spain) and used at
10-8–10-6 M.
Escherichia coli 055:B5 LPS was purchased from Sigma
(Barcelona, Spain) and used at 10 ng/ml. The Janus kinase (JAK)2/3
inhibitor AG-490 and the mitogen-activated protein/extracellular
signal-regulated kinase kinase (MEK)1/2 inhibitor U0126 were purchased
from Calbiochem (San Diego, CA) and used at 30 µg/ml to 30 ng/ml
(AG-490) and 2.5 µM (U0126).
Cells
Human PBMC were isolated from buffy coats from normal donors over a Lymphoprep (Nycomed, Oslo, Norway) gradient according to standard procedures. Monocytes were purified from PBMC by a 1-h adherence step at 37°C in complete medium. Nonadherent cells were washed off by extensive washing with PBS and the remaining adherent cells (>90% monocytes, as determined by flow cytometric analysis of forward scatter/side scatter, CD14 and CD11c staining) were immediately subjected to the DC differentiation protocol as previously described (6, 7, 18, 19). Briefly, monocytes were resuspended at 0.5–1 x 106 cells/ml and cultured in RPMI 1640 supplemented with 10% FCS, 25 mM HEPES, and 2 mM glutamine (complete medium) containing 1000 U/ml GM-CSF and 1000 U/ml IL-4. Cells were cultured for 5–7 days, with cytokine addition every second day, to obtain a population of immature MDDC. For maturation, immature MDDC were treated with LPS at 10 ng/ml.
Flow cytometry and Abs
Cellular phenotypic analysis was conducted by indirect immunofluorescence. mAbs used for cell surface staining included T3b (anti-CD3), TS1/2 (anti-MHC class II), HB1/5 (anti-CD83; Immunotech, Marseille, France), HC1/1 (anti-CD11c), UCH-M1 (anti-CD14; Santa Cruz Biotechnology, Santa Cruz, CA), and BL6 (anti-CD1a; Immunotech). All incubations were done in the presence of 50 µg/ml human IgG to prevent binding through the Fc portion of the Abs. The supernatant from the myeloma P3x63 (X63) was always included as a negative control. Flow cytometry analysis was performed with an EPICS-CS (Coulter Científica, Madrid, Spain) using log amplifiers. Where indicated, results are expressed as expression index: percentage of marker-positive cells multiplied by their mean fluorescence intensity (MFI).
Immunofluorescence staining
LPS-treated MDDC were resuspended in complete medium and allowed to adhere onto poly-L-lysine-coated coverslips (50 x 103 cells/coverslip) for 60 min. Cells were fixed in 3.7% formaldehyde in PBS (10 min at room temperature), permeabilized with 0.2% Triton X-100 (10 min at room temperature), and processed for immunofluorescence. Preparations were double-stained with the MR-1 anti-CD209 Ab and FITC-phalloidin (Sigma) for 45 min at room temperature, followed by an incubation with Cy3 goat anti-mouse Ab (Jackson ImmunoResearch Laboratories, West Grove, PA) diluted 1/500 in PBS. Additional Abs included TS1/2 (anti-MHC class II) and the anti-CD83 Ab HB1/5, which specifically reacts with mature MDDC. Coverslips were mounted in fluorescent mounting medium (DAKO, Glostrup, Denmark) and representative fields of cells were photographed through an oil immersion lens on a Nikon Eclipse E800 microscope (Nikon, Melville, NY) equipped for epifluorescence. Cells were also photographed using Nomarski optics.
Northern blot
After extensive washing in PBS, cells were harvested and total cellular RNA was isolated using RNeasy columns (Qiagen, Hilden, Germany) following the manufacturer’s recommendations. After confirming RNA integrity, denatured RNA (10 µg) was size-fractionated on formaldehyde-containing 1% agarose gels in the presence of ethidium bromide. Then, RNA was transferred overnight onto nitrocellulose membranes with 20x SSC. Prehybridization was conducted overnight at 42°C in 50% formamide, 5x SSC, 5x Denhardt’s, 50 mM sodium phosphate (pH 6.5), and 250 µg/ml denatured salmon sperm DNA. Membranes were hybridized for 16 h at 42°C in the same solution containing 106 cpm/ml oligo-labeled probe. Blots were sequentially washed in 2x SSC, 0.5% SDS at room temperature, and in 0.3x SSC, 0.5% SDS at 65°C, and exposed to x-ray film at -70°C. Detection of DC-SIGN mRNA was accomplished using the whole coding region of the DC-SIGN cDNA as probe (10).
Generation of stable DC-SIGN transfectants in K562 cells
The whole coding region of DC-SIGN was initially obtained by RT-PCR using oligonucleotides 5'-GGGAATTCAGAGTGGGGTGACATGAGTGAC-3' and 5'-CCCCAAGCTTGTGAAGTTCTGCTACGCAGGAG-3' as primers, where italicized letters mark the initiation and termination codons and underlined residues represent additional sequences containing EcoRI or HindIII restriction sites. Two micrograms of total RNA from immature MDDC was reverse transcribed in a total volume of 20 µl of amplification buffer (50 mM Tris-HCl (pH 8.2), 5 mM MgCl2, 10 mM DTT, 50 mM KCl, 1 mM of each deoxynucleotide, 0.5 µM random hexamers) including RNAsin and avian myeloblastosis virus reverse transcriptase (Promega, Madison, WI) at 1 U/µl. The mixture was incubated at 42°C for 60 min followed by a 30-min incubation at 52°C, and the final volume was taken to 100 µl with water. Amplification of the full-length DC-SIGN mRNA was conducted using 5 µl of the cDNA synthesis reaction in 50 µl of a solution containing 0.2 mM of each deoxynucleotide, 1 µM of each oligonucleotide primer, and 2.5 U of Pfu DNA polymerase (Stratagene, La Jolla, CA). The resulting fragment was digested with EcoRI and HindIII and gel purified and ligated into EcoRI- and HindIII-digested pCDNA3.1- to generate pCDNA3.1-DC-SIGN. Transfection of pCDNA3.1-DC-SIGN in K562 cells was accomplished using Superfect (Qiagen), and selection of transfected cells was done using G418 (300 µg/ml). Stable DC-SIGN expression of the selected population (K562-CD209) was verified using the anti-DC-SIGN Ab AZN-D1 (provided by Dr. Y. van Kooyk, Free University Medical Center, Amsterdam, The Netherlands) (11).
Generation of anti-DC-SIGN mAbs
BALB/c mice received three i.p. injections of 106 immature MDDC and a final i.v. boost with 4 x 106 immature MDDC. Three days later, spleen was removed and splenocytes were fused to SP2 cells at a 2:1 ratio using PEG 1500 (Sigma). Cells were split in eight 96-well plates and selection for hybridomas was accomplished with azaserine and hypoxanthine. Once hybridoma growth was evident, 100 µl of supernatant was removed from each well and subjected to screening for anti-DC-SIGN Abs. To that end, hybridoma supernatants were analyzed by indirect immunofluorescence against a 1/1 mixture of K562 and K562-CD209 cells, and those producing a bimodal distribution of cell fluorescence intensity were selected for further study. After two rounds of cloning, a single hybridoma (6G6) was obtained whose mAb (MR-1) specifically recognized K562-CD209 transfectants as well as immature MDDC.
HIV binding assays
Cells grown under distinct culture conditions (106/well) were pretreated or not with distinct dilutions (1/100, 1/500, 1/2500, 1/10000) of ascitic fluid of the anti-DC-SIGN MR-1 or the anti-CD3 T3b Ab, for 1 h at 4°C. Then HIV-1NL4.3 was added to the wells (multiplicity of infection = 1) and incubated for 3 h at 37°C. Cells were washed five times with 2% FCS in PBS and lysed with 0.5% Triton X-100, and HIV-1 binding was evaluated by an Ag p24 assay (Innogenetics, Barcelona, Spain). For each assay, trypsin was added to parallel wells to control for nonspecific binding.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The full-length DC-SIGN cDNA was amplified from immature MDDC
total RNA, and the resulting 1,239-bp fragment was inserted into the
pCDNA3.1- expression plasmid and used to generate stable DC-SIGN
transfectants in K562 cells (K562-CD209). Expression of DC-SIGN in
K562-CD209 was demonstrated using the previously described AZN-D1
anti-DC-SIGN mAb (11) (Fig. 1
A). K562 and K562-CD209 cells
were mixed (1/1) and the resulting population was used in the screening
for hybridomas producing anti-DC-SIGN Abs. One hybridoma yielded a
flow cytometry profile compatible with anti-DC-SIGN reactivity
(Fig. 1B), and it was selected and grown for further
studies. After two rounds of cloning by limiting dilution, it became
evident that the selected hybridoma produced an Ab (hereafter termed
MR-1) that specifically recognized K562-CD209 cells while it was
completely unreactive against untransfected K562 cells (Fig. 1C). The DC-SIGN-specific reactivity of the MR-1 Ab was
further demonstrated in flow cytometry and immunofluorescence analysis
(see Fig. 1D and below). MR-1 specifically recognized
LPS-matured MDDC, which exhibited a high level of expression of MHC
class II molecules and the mature MDDC marker CD83. By contrast, MR-1
did not recognize PBL, PHA-activated PBL, monocytes, granulocytes, or
endothelial cells (data not shown).
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The availability of the MR-1 Ab allowed us to dissect the changes
in DC-SIGN expression that take place during DC differentiation. To
that end, peripheral blood monocytes were isolated and differentiated
along the macrophage, immature MDDC, or Langerhans cell-like
(20) pathways in the presence of M-CSF, GM-CSF plus IL-4,
or GM-CSF plus IL-4 plus TGF-, respectively. As shown in Fig. 2, M-CSF-treated monocytes retained CD14
on the cell surface and did not acquire CD1a or DC-SIGN expression
after a 6-day treatment period. By contrast, immature MDDC and
Langerhans-like cells lost expression of CD14 and acquired a high level
of CD1a and DC-SIGN expression (Fig. 2). In all cases, GM-CSF plus
IL-4-treated monocytes (immature MDDC) showed a higher level of DC-SIGN
expression than those cultured in the presence of GM-CSF plus IL-4 plus
TGF- (Fig. 2), suggesting an inhibitory effect of TGF- on the
DC-SIGN expression (see below). Therefore, and in agreement with
previous studies (11), DC-SIGN appears to be specifically
induced along the DC differentiation pathway.
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A). By contrast, IL-4-treated
monocytes lost CD14 expression and, although they did not acquire CD1a,
exhibited a moderate-to-high level of DC-SIGN expression (56%
MR-1+ cells and 1.4 MFI) (Fig. 3A),
suggesting that DC-SIGN induction during MDDC differentiation is
primarily IL-4 mediated. The combined addition of GM-CSF and IL-4 led
to disappearance of CD14 and acquisition of CD1a and yielded the
highest DC-SIGN expression after 48 h (78%
MR-1+ cells and 2.7 MFI) (Fig. 3A).
The induction of DC-SIGN expression by IL-4 was found to be dose
dependent, with IL-4 yielding maximum levels of DC-SIGN expression at
200 U/ml, although its effects were observed with concentrations as low
as 10 U/ml (Fig. 3B). Altogether these results indicate that
the DC-SIGN induction during monocyte-MDDC differentiation is primarily
triggered by IL-4 and that GM-CSF enhances the IL-4-dependent induction
of DC-SIGN, suggesting that both factors exert a cooperative effect on
DC-SIGN expression.
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A, a single exposure to
either IL-4 or GM-CSF plus IL-4 was enough to induce DC-SIGN expression
after 24 h, and its expression reached the highest levels after
36–48 h (Fig. 4A). This result was further confirmed upon
detection of DC-SIGN mRNA during the initial stages of monocyte-MDDC
differentiation. DC-SIGN mRNA was initially detected 6 h after
GM-CSF plus IL-4 addition, peaked after 24–36 h, and started to
decline thereafter: 48 h after GM-CSF plus IL-4 treatment, DC-SIGN
mRNA level was 60% of that observed after 24 h of cytokine
addition (Fig. 4B). Therefore, DC-SIGN expression is
primarily dependent on IL-4 and is acquired during the initial stages
of the monocyte-MDDC differentiation pathway.
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The IL-4-dependent induction of several genes is known to be
primarily mediated through activation of the JAK-STAT pathway, with
STAT6 being the key transcription factor mediating IL-4 inducibility
(21). The involvement of the JAK-STAT signaling route in
the IL-4-dependent induction of DC-SIGN in monocytes was initially
evaluated by the use of tyrphostin AG490, an specific inhibitor of JAK2
and JAK3 activation (22, 23). Induction of
DC-SIGN by IL-4 was completely abrogated in the presence of
AG-490 concentrations known to specifically inhibit JAK2 and JAK3 (Fig. 5A), and further dilution of
the inhibitor still prevented a full induction of DC-SIGN (Fig. 5A). Conversely, AG-490 did not affect the expression
of CD14 (Fig. 5A). Similarly, the GM-CSF plus IL-4-triggered
induction of DC-SIGN was inhibited by AG-490 in a dose-dependent manner
(Fig. 5B). In this case, the expression of CD1a was affected
in a similar fashion, while CD14 expression was not affected (Fig. 5B). In parallel experiments, the MEK1/2 inhibitor U0126
also diminished the induction of DC-SIGN caused by either IL-4 or the
combination of GM-CSF plus IL-4 (Fig. 5), while it left unaltered the
expression of CD14 and increased the expression of CD1a in response to
GM-CSF plus IL-4 (Fig. 5). Altogether, these results suggest a role for
the MEK-extracellular signal-regulated kinase (ERK) and JAK-STAT
pathways in the induction of DC-SIGN by IL-4.
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or IFN-
through transcriptional and posttranscriptional mechanisms
(24). To find out whether DC-SIGN is subjected to a
similar type of regulation, and because initial experiments revealed
that IFN- or IFN- did not induce DC-SIGN on monocytes (data not
shown), DC differentiation was induced in the presence of either type
of IFN. As shown in Fig. 6A,
IFN- greatly reduced the IL-4-dependent induction of DC-SIGN (88%
MR-1+ cells and 5.6 MFI vs 26%
MR-1+ cells and 0.7 MFI). The inhibitory effect
of IFN- could be seen at concentrations as low as 50 U/ml (Fig. 6B), demonstrating that the IL-4 inducibility of DC-SIGN
expression is extremely sensitive to the presence of IFN-. Although
to a lower extent, the IFN- inhibitory effect was also observed when
peripheral blood monocytes were treated with GM-CSF plus IL-4 (94%
MR-1+ cells and 13 MFI vs 60%
MR-1+ cells and 1.9 MFI) (Fig. 6A).
IFN- also reduced the IL-4-inducible expression of DC-SIGN, but its
inhibitory effect was weaker than that of IFN- (88%
MR-1+ cells and 5.6 MFI vs 64%
MR-1+ cells and 2 MFI) (Fig. 6A).
Unlike IFN-, IFN- was only capable of preventing the
IL-4-mediated induction of DC-SIGN, while it had no effect on the
DC-SIGN expression induced by IL-4 and GM-CSF (Fig. 6A).
These results confirm the cooperative effect of GM-CSF and IL-4 on
DC-SIGN induction and indicate that type I and type II IFN
differentially affect DC-SIGN induction during monocyte-MDDC
differentiation. Therefore, like other IL-4-regulated genes, induction
of DC-SIGN is negatively regulated by either type of IFN. Besides,
because treatment of DC-SIGN-expressing immature MDDC with either
IFN- or IFN- had no major effect on DC-SIGN expression (Fig. 6C), the negative regulatory role of IFNs appears to be
exerted at an early time point during DC differentiation, possibly by
inhibiting the STAT-mediated signaling cascades initiated upon IL-4
treatment.
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and dexamethasone are negative regulatory factors for
DC-SIGN expression
TGF- is an essential factor for Langerhans cell generation
(25), and TGF--based protocols have been established
that generate Langerhans cell-like cells from monocytes
(20). Given the lower DC-SIGN expression obtained upon
Langerhans cell differentiation (Fig. 2
), we tested whether TGF- had
any effect on the inducible DC-SIGN expression. At a concentration of
10 ng/ml, TGF- greatly reduced the IL-4-induced DC-SIGN expression
(from 74% MR-1+ cells and 2.2 MFI to 33% and
0.7 MFI) (Fig. 7A). To a lower
extent, TGF- also reduced the expression of DC-SIGN induced upon
treatment with GM-CSF plus IL-4 (86% MR-1+ and
4.9 MFI vs 67% and 1.8 MFI) (Fig. 7A). The TGF-
inhibitory effect could be observed as early as 24 h and was
evident at all time points analyzed (Fig. 7B). Therefore,
TGF- has a direct negative influence on the IL-4-dependent induction
of DC-SIGN, which might explain the lower DC-SIGN expression observed
when monocytes differentiate in vitro along the Langerhans cell
differentiation pathway.
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C).
Moreover, the induction of DC-SIGN by IL-4 was completely prevented in
the presence of 10-6 M dexamethasone (Fig. 7D), and identical inhibitory effects were obtained with
10-7 and 10-8 M
dexamethasone (data not shown), underscoring the physiological
significance of this inhibitory effect. Therefore, dexamethasone, a
well-known inhibitor of the monocyte-MDDC differentiation pathway,
inhibits the induction of DC-SIGN that takes place during the process,
and completely prevents the IL-4-triggered DC-SIGN expression.
IFN, TGF-, and dexamethasone prevent the induction of
DC-SIGN mRNA
To determine the mechanisms responsible for the effects of
IFN-, TGF-, and dexamethasone on the DC-SIGN inducibility, the
level of DC-SIGN mRNA was analyzed by Northern blot. As predicted from
the cell surface expression results, DC-SIGN mRNA was absent in
peripheral blood monocytes either untreated or exposed to IFN- (Fig. 8A). By contrast, monocyte
treatment with IL-4 for 6 h led to induction of DC-SIGN mRNA (Fig. 8A). Moreover, although GM-CSF alone had a minor impact on
DC-SIGN mRNA, it further enhanced the level of DC-SIGN mRNA induced by
IL-4 (Fig. 8A), confirming the collaborative action of both
factors on DC-SIGN expression. The inhibitory effect of IFN- on
DC-SIGN induction was also observed at the mRNA level, because IFN-
considerably reduced the DC-SIGN mRNA level yielded upon IL-4 treatment
(Fig. 8A). The negative effects of dexamethasone and TGF-
on DC-SIGN expression were also confirmed by analysis of the DC-SIGN
mRNA level in monocytes from two independent donors. As shown in Fig. 8B, the presence of either TGF- or dexamethasone greatly
prevented the induction of DC-SIGN mRNA produced by the combination of
GM-CSF plus IL-4. All these results indicate that, in monocytes,
DC-SIGN mRNA level is greatly up-regulated through the combined action
of GM-CSF and IL-4, thus explaining the induction of DC-SIGN cell
surface expression along the GM-CSF plus IL-4-driven monocyte-MDDC
differentiation pathway, and that IFN-, TGF-, and dexamethasone
inhibit the acquisition of DC-SIGN expression by decreasing the levels
of DC-SIGN mRNA.
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To evaluate the functional relevance of the positive and
negative regulators of DC-SIGN expression, we tested the
DC-SIGN-dependent HIV-binding ability of differentiating MDDC in the
presence of TGF-, IFN-, or dexamethasone. Treatment of monocytes
with either IL-4 or GM-CSF plus IL-4 for 48 h, a time point at
which DC-SIGN induction has taken place, considerably increased
HIV-binding ability, as measured by HIV p24 Ag determination (Fig. 9A). HIV binding was
specifically and dose-dependently inhibited by the MR-1 Ab, thus
confirming that the increased HIV binding was DC-SIGN dependent (Fig. 9B). In addition, the presence of either TGF-, IFN-,
or dexamethasone, all of which prevented DC-SIGN induction (
Figs. 6–8), greatly inhibited the IL-4- or GM-CSGF plus IL-4-induced
increase in HIV binding (Fig. 9A). Therefore, TGF-,
IFN-, and dexamethasone block the induction of DC-SIGN caused by
IL-4 or during the monocyte-MDDC differentiation and, consequently,
prevent the acquisition of DC-SIGN-dependent functions.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IFNs, and inhibitors
of the monocyte-MDDC transition have been identified as negative
regulators of DC-SIGN expression and, as a consequence, inhibit the
DC-SIGN-dependent binding of HIV-1 to differentiating MDDC. Altogether,
these results indicate that DC-SIGN expression is regulated by numerous
cytokines and growth factors and suggest that DC-SIGN, considered as a
MDDC differentiation marker, is specifically expressed on IL-4-treated
monocytes. The generation of DCs from monocytes depends critically on IL-4 (6, 7, 8), which, based on its capacity to inhibit macrophage colony formation (28), is thought to function mainly by suppressing differentiation along the macrophage pathway. However, the IL-4 inducibility of DC-SIGN and the relevance of the DC-SIGN activities indicate that IL-4 not only suppresses the monocyte/macrophage lineage but actively promotes the differentiation of monocytes along the DC lineage. In this regard, and because of its DC-SIGN-inducing function, IL-4 appears to be required for MDDC to acquire their full repertoire of migratory and T cell-interacting capabilities, because DC-SIGN mediates both DC trafficking (through binding to ICAM-2) and the DC-T cell interactions during the generation of an immune response (through binding to ICAM-3) (29).
IL-4 signals through activation of STAT6 and, in fact, lymphocytes from
STAT6-/- mice are unable to up-regulate
IL-4-responsive genes (reviewed in Ref. 21). STAT6
mediates the IL-4 inducibility of several genes (30, 31)
that exhibit STAT6-binding elements within their gene regulatory
regions (32, 33). Accordingly, it is tempting to speculate
that DC-SIGN induction is directly regulated by STAT6, a hypothesis
supported by 1) the negative effect of the JAK2/3 inhibitor AG-490 on
DC-SIGN expression; 2) the presence of consensus STAT-binding elements
within the DC-SIGN gene proximal regulatory region (M. Relloso and
A. L. Corbí, unpublished observations); and 3) the ability
of IFN- to inhibit DC-SIGN expression. The negative regulatory
effect of IFN- on the expression of several IL-4-regulated genes is
now well established (reviewed in Ref. 24), and there are
evidences that IFN- and IFN- suppress IL-4-inducible gene
expression by inhibiting tyrosine phosphorylation and nuclear
translocation of STAT6 (34), possibly via
suppressors of cytokine
signaling expression (35). Therefore, it
is conceivable that inhibition of IL-4-dependent STAT6 activation might
contribute to the reduced DC-SIGN expression observed in the presence
of IFN-. By contrast, and despite the capacity of TGF- to inhibit
JAK-STAT activation in other systems (36), the inhibitory
effect of TGF- on DC-SIGN induction might be STAT6 independent
because TGF- fails to suppress STAT6 activation by IL-4 on monocytes
(35). In any event, because IL-4 treatment does not lead
to the appearance of DC-SIGN on PBL or endothelial cells (data not
shown), it appears that cell type-specific factors distinct from STAT6
are also involved in the regulation of DC-SIGN expression.
In addition to IFN and TGF-, dexamethasone also counteracts the
positive effect of IL-4 on DC-SIGN expression. Dexamethasone, which
inhibits monocyte-MDDC differentiation (26, 27), not only
blocks the GM-CSF plus IL-4-dependent acquisition of CD1a but also that
of DC-SIGN. Because dexamethasone is an NF-
B inhibitor (37, 38) and NF-B activity greatly increases during MDDC
differentiation (39), it is possible that DC-SIGN
expression is positively regulated by NF-B factors. This alternative
is not supported by our findings that classical NF-B activators such
as LPS or TNF- do not up-regulate, but reduce, DC-SIGN expression,
and that the DC-SIGN proximal promoter is not transactivated by NF-B
proteins (A. L. Corbí, unpublished observations). An
alternative possibility, which we favor, is that dexamethasone inhibits
DC-SIGN expression by blocking IL-4-triggered intracellular signaling.
The ability of dexamethasone to suppress JAK-STAT signaling has been
recently reported (40) and indicates that dexamethasone is
capable of inhibiting IL-4-induced STAT6 activation on T lymphocytes.
Because dexamethasone abolishes the induction of DC-SIGN by IL-4, which
by itself does not promote MDDC differentiation, it is reasonable to
conclude that dexamethasone prevents DC-SIGN induction by impairing
IL-4 signaling and independently of its inhibitory effect on the
monocyte-MDDC transition.
Finally, it is worth noting that DC-SIGN expression is oppositely
regulated by IL-4 and IFN-, whose production is mutually exclusive
upon activation and polarization of naive T lymphocytes. IL-4 is the
driving cytokine for Th2 polarization and a major product of Th2
lymphocytes, while IFN- is the most relevant product of Th1 cells
(4, 5). Their differential production by Th1 and Th2 cells
underlies the specific features of helper-dependent immune responses:
IFN- (and other Th1 cytokines) promotes neutrophil recruitment and
macrophage activation, thus leading to inflammatory responses, while
IL-4 (and other Th2 cytokines) limits Th1-mediated inflammatory
responses, thus preventing excessive tissue destruction and restraining
inflammation. Consequently, while promoting macrophage differentiation
and activation, Th1 lymphocytes would prevent the acquisition of
DC-SIGN expression by monocytes within inflamed tissues, while DC-SIGN
expression would be induced on monocytes during Th2 responses or once
Th2 cytokines are produced to down-regulate Th1 immune responses. Thus,
if DC-SIGN expression marks the differentiation of monocytes into DCs,
a phenomenon known to occur in vivo (41), MDDC production
would depend on the interplay between Th1- and Th2-derived cytokines
within an inflamed tissue. According to this hypothesis, monocyte
differentiation into DCs would be favored once inflammatory responses
are down-regulated, thus allowing the inflamed tissue to regain their
normal complement of DCs. Further studies on the mechanisms controlling
DC-SIGN expression are required to determine whether its expression on
monocytes correlates with DC differentiation and/or the distinct stages
during inflammatory responses.
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Acknowledgments |
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Footnotes |
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2 Current address: University of California, Davis, CA.
3 Address correspondence and reprint requests to Dr. Angel L. Corbí, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Velázquez 144, 28006 Madrid, Spain. E-mail address: acorbi{at}cib.csic.es
4 Abbreviations used in this paper: DC, dendritic cell; DC-SIGN, DC-specific ICAM-3 grabbing nonintegrin; MDDC, monocyte-derived DC; JAK, Janus kinase; ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein/ERK kinase; MFI, mean fluorescence intensity.
Received for publication September 10, 2001. Accepted for publication January 14, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. J. Exp. Med. 179:1109.. J. Exp. Med. 184:695.1, in the presence of granulocyte/macrophage colony-stimulating factor and interleukin 4, induces differentiation of human peripheral blood monocytes into dendritic Langerhans cells. J. Exp. Med. 187:961.1 in Langerhans cell biology: the skin of transforming growth factor 1 null mice is devoid of epidermal Langerhans cells. J. Exp. Med. 184:2417.
RII receptor (CD23) on normal human B lymphocytes. J. Exp. Med. 165:1459. and Fc receptor II (CD23b) genes activated via binding of an interleukin-4-induced transcription factor to a novel responsive element. Eur. J. Immunol. 23:3066.[Medline]
B and STAT6 in human airway epithelial cells. J. Immunol. 163:6876. and IL-10 inhibit induction of IL-1 receptor type I and type II gene expression by IL-4 and IL-13 on human monocytes. J. Immunol. 159:6226.[Abstract]
inhibits IL-12-induced activation of Janus kinase-STAT pathway in T lymphocytes. J. Immunol. 161:1772.B in mediation of immunosuppression by glucocorticoids. Science 270:283.B activity through induction of IB synthesis. Science 270:286.B and octamer factors is a hallmark of the generation and maturation of dendritic cells. Blood 95:277.This article has been cited by other articles:
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G. Malcherek, L. Mayr, P. Roda-Navarro, D. Rhodes, N. Miller, and J. Trowsdale The B7 Homolog Butyrophilin BTN2A1 Is a Novel Ligand for DC-SIGN J. Immunol., September 15, 2007; 179(6): 3804 - 3811. [Abstract] [Full Text] [PDF]
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 V. Roulet, A.-P. Satie, A. Ruffault, A. L. Tortorec, H. Denis, O. Guist'hau, J.-J. Patard, N. Rioux-Leclerq, J. Gicquel, B. Jegou, et al. Susceptibility of Human Testis to Human Immunodeficiency Virus-1 Infection in Situ and in Vitro Am. J. Pathol., December 1, 2006; 169(6): 2094 - 2103. [Abstract] [Full Text] [PDF]
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F. O. Martinez, S. Gordon, M. Locati, and A. Mantovani Transcriptional Profiling of the Human Monocyte-to-Macrophage Differentiation and Polarization: New Molecules and Patterns of Gene Expression J. Immunol., November 15, 2006; 177(10): 7303 - 7311. [Abstract] [Full Text] [PDF]
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P. Sun, C. M. Celluzzi, M. Marovich, H. Subramanian, M. Eller, S. Widjaja, D. Palmer, K. Porter, W. Sun, and T. Burgess CD40 Ligand Enhances Dengue Viral Infection of Dendritic Cells: A Possible Mechanism for T Cell-Mediated Immunopathology J. Immunol., November 1, 2006; 177(9): 6497 - 6503. [Abstract] [Full Text] [PDF]
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 C.W. Cutler and R. Jotwani Dendritic Cells at the Oral Mucosal Interface Journal of Dental Research, August 1, 2006; 85(8): 678 - 689. [Abstract] [Full Text] [PDF]
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W. K. Lai, P. J. Sun, J. Zhang, A. Jennings, P. F. Lalor, S. Hubscher, J. A. McKeating, and D. H. Adams Expression of DC-SIGN and DC-SIGNR on Human Sinusoidal Endothelium: A Role for Capturing Hepatitis C Virus Particles Am. J. Pathol., July 1, 2006; 169(1): 200 - 208. [Abstract] [Full Text] [PDF]
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S. Rutella, G. Bonanno, A. Procoli, A. Mariotti, D. G. de Ritis, A. Curti, S. Danese, G. Pessina, S. Pandolfi, F. Natoni, et al. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features Blood, July 1, 2006; 108(1): 218 - 227. [Abstract] [Full Text] [PDF]
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E. Caparros, P. Munoz, E. Sierra-Filardi, D. Serrano-Gomez, A. Puig-Kroger, J. L. Rodriguez-Fernandez, M. Mellado, J. Sancho, M. Zubiaur, and A. L. Corbi DC-SIGN ligation on dendritic cells results in ERK and PI3K activation and modulates cytokine production Blood, May 15, 2006; 107(10): 3950 - 3958. [Abstract] [Full Text] [PDF]
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 I. Caminschi, A. J Corbett, C. Zahra, M. Lahoud, K. M Lucas, M. Sofi, D. Vremec, T. Gramberg, S. Pohlmann, J. Curtis, et al. Functional comparison of mouse CIRE/mouse DC-SIGN and human DC-SIGN Int. Immunol., May 1, 2006; 18(5): 741 - 753. [Abstract] [Full Text] [PDF]
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I. I. Slukvin, M. A. Vodyanik, J. A. Thomson, M. E. Gumenyuk, and K.-D. Choi Directed Differentiation of Human Embryonic Stem Cells into Functional Dendritic Cells through the Myeloid Pathway. J. Immunol., March 1, 2006; 176(5): 2924 - 2932. [Abstract] [Full Text] [PDF]
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G. Rappocciolo, F. J. Jenkins, H. R. Hensler, P. Piazza, M. Jais, L. Borowski, S. C. Watkins, and C. R. Rinaldo Jr DC-SIGN Is a Receptor for Human Herpesvirus 8 on Dendritic Cells and Macrophages J. Immunol., February 1, 2006; 176(3): 1741 - 1749. [Abstract] [Full Text] [PDF]
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A. Granelli-Piperno, I. Shimeliovich, M. Pack, C. Trumpfheller, and R. M. Steinman HIV-1 Selectively Infects a Subset of Nonmaturing BDCA1-Positive Dendritic Cells in Human Blood J. Immunol., January 15, 2006; 176(2): 991 - 998. [Abstract] [Full Text] [PDF]
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A. Granelli-Piperno, A. Pritsker, M. Pack, I. Shimeliovich, J.-F. Arrighi, C. G. Park, C. Trumpfheller, V. Piguet, T. M. Moran, and R. M. Steinman Dendritic Cell-Specific Intercellular Adhesion Molecule 3-Grabbing Nonintegrin/CD209 Is Abundant on Macrophages in the Normal Human Lymph Node and Is Not Required for Dendritic Cell Stimulation of the Mixed Leukocyte Reaction J. Immunol., October 1, 2005; 175(7): 4265 - 4273. [Abstract] [Full Text] [PDF]
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A. Dominguez-Soto, A. Puig-Kroger, M. A. Vega, and A. L. Corbi PU.1 Regulates the Tissue-specific Expression of Dendritic Cell-specific Intercellular Adhesion Molecule (ICAM)-3-grabbing Nonintegrin J. Biol. Chem., September 30, 2005; 280(39): 33123 - 33131. [Abstract] [Full Text] [PDF]
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M. C. Gagliardi, R. Teloni, F. Giannoni, M. Pardini, V. Sargentini, L. Brunori, L. Fattorini, and R. Nisini Mycobacterium bovis Bacillus Calmette-Guerin infects DC-SIGN- dendritic cell and causes the inhibition of IL-12 and the enhancement of IL-10 production J. Leukoc. Biol., July 1, 2005; 78(1): 106 - 113. [Abstract] [Full Text] [PDF]
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S. Patterson, H. Donaghy, P. Amjadi, B. Gazzard, F. Gotch, and P. Kelleher Human BDCA-1-Positive Blood Dendritic Cells Differentiate into Phenotypically Distinct Immature and Mature Populations in the Absence of Exogenous Maturational Stimuli: Differentiation Failure in HIV Infection J. Immunol., June 15, 2005; 174(12): 8200 - 8209. [Abstract] [Full Text] [PDF]
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K. B. Gurney, J. Elliott, H. Nassanian, C. Song, E. Soilleux, I. McGowan, P. A. Anton, and B. Lee Binding and Transfer of Human Immunodeficiency Virus by DC-SIGN+ Cells in Human Rectal Mucosa J. Virol., May 1, 2005; 79(9): 5762 - 5773. [Abstract] [Full Text] [PDF]
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G. de la Rosa, M. Yanez-Mo, R. Samaneigo, D. Serrano-Gomez, L. Martinez-Munoz, E. Fernandez-Ruiz, N. Longo, F. Sanchez-Madrid, A. L. Corbi, and P. Sanchez-Mateos Regulated recruitment of DC-SIGN to cell-cell contact regions during zymosan-induced human dendritic cell aggregation J. Leukoc. Biol., May 1, 2005; 77(5): 699 - 709. [Abstract] [Full Text] [PDF]
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L. Riol-Blanco, N. Sanchez-Sanchez, A. Torres, A. Tejedor, S. Narumiya, A. L. Corbi, P. Sanchez-Mateos, and J. L. Rodriguez-Fernandez The Chemokine Receptor CCR7 Activates in Dendritic Cells Two Signaling Modules That Independently Regulate Chemotaxis and Migratory Speed J. Immunol., April 1, 2005; 174(7): 4070 - 4080. [Abstract] [Full Text] [PDF]
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D. Jimenez, P. Roda-Navarro, T. A. Springer, and J. M. Casasnovas Contribution of N-Linked Glycans to the Conformation and Function of Intercellular Adhesion Molecules (ICAMs) J. Biol. Chem., February 18, 2005; 280(7): 5854 - 5861. [Abstract] [Full Text] [PDF]
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B. Vasir, D. Avigan, Z. Wu, K. Crawford, S. Turnquist, J. Ren, and D. Kufe Dendritic Cells Induce MUC1 Expression and Polarization on Human T Cells by an IL-7-Dependent Mechanism J. Immunol., February 15, 2005; 174(4): 2376 - 2386. [Abstract] [Full Text] [PDF]
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A. Marzi, T. Gramberg, G. Simmons, P. Moller, A. J. Rennekamp, M. Krumbiegel, M. Geier, J. Eisemann, N. Turza, B. Saunier, et al. DC-SIGN and DC-SIGNR Interact with the Glycoprotein of Marburg Virus and the S Protein of Severe Acute Respiratory Syndrome Coronavirus J. Virol., November 1, 2004; 78(21): 12090 - 12095. [Abstract] [Full Text] [PDF]
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D. Serrano-Gomez, A. Dominguez-Soto, J. Ancochea, J. A. Jimenez-Heffernan, J. A. Leal, and A. L. Corbi Dendritic Cell-Specific Intercellular Adhesion Molecule 3-Grabbing Nonintegrin Mediates Binding and Internalization of Aspergillus fumigatus Conidia by Dendritic Cells and Macrophages J. Immunol., November 1, 2004; 173(9): 5635 - 5643. [Abstract] [Full Text] [PDF]
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 L. Rieger, A. Honig, M. Sutterlin, M. Kapp, J. Dietl, P. Ruck, and U. Kammerer Antigen-Presenting Cells in Human Endometrium During the Menstrual Cycle Compared to Early Pregnancy Reproductive Sciences, October 1, 2004; 11(7): 488 - 493. [Abstract] [PDF]
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 H. Niiya, T. Azuma, L. Jin, N. Uchida, A. Inoue, H. Hasegawa, S. Fujita, M. Tohyama, K. Hashimoto, and M. Yasukawa Transcriptional downregulation of DC-SIGN in human herpesvirus 6-infected dendritic cells J. Gen. Virol., September 1, 2004; 85(9): 2639 - 2642. [Abstract] [Full Text] [PDF]
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N. Sanchez-Sanchez, L. Riol-Blanco, G. de la Rosa, A. Puig-Kroger, J. Garcia-Bordas, D. Martin, N. Longo, A. Cuadrado, C. Cabanas, A. L. Corbi, et al. Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells Blood, August 1, 2004; 104(3): 619 - 625. [Abstract] [Full Text] [PDF]
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 K. C. Roy, G. Bandyopadhyay, S. Rakshit, M. Ray, and S. Bandyopadhyay IL-4 alone without the involvement of GM-CSF transforms human peripheral blood monocytes to a CD1adim, CD83+ myeloid dendritic cell subset J. Cell Sci., July 15, 2004; 117(16): 3435 - 3445. [Abstract] [Full Text] [PDF]
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M. J.-Y. Ploquin, O. M. Diop, N. Sol-Foulon, L. Mortara, A. Faye, M. A. Soares, E. Nerrienet, R. Le Grand, Y. Van Kooyk, A. Amara, et al. DC-SIGN from African Green Monkeys Is Expressed in Lymph Nodes and Mediates Infection in trans of Simian Immunodeficiency Virus SIVagm J. Virol., January 15, 2004; 78(2): 798 - 810. [Abstract] [Full Text] [PDF]
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M. Colmenares, A. L. Corbi, S. J. Turco, and L. Rivas The Dendritic Cell Receptor DC-SIGN Discriminates among Species and Life Cycle Forms of Leishmania J. Immunol., January 15, 2004; 172(2): 1186 - 1190. [Abstract] [Full Text] [PDF]
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 F. Lasala, E. Arce, J. R. Otero, J. Rojo, and R. Delgado Mannosyl Glycodendritic Structure Inhibits DC-SIGN-Mediated Ebola Virus Infection in cis and in trans Antimicrob. Agents Chemother., December 1, 2003; 47(12): 3970 - 3972. [Abstract] [Full Text] [PDF]
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W. B. Klimstra, E. M. Nangle, M. S. Smith, A. D. Yurochko, and K. D. Ryman DC-SIGN and L-SIGN Can Act as Attachment Receptors for Alphaviruses and Distinguish between Mosquito Cell- and Mammalian Cell-Derived Viruses J. Virol., November 15, 2003; 77(22): 12022 - 12032. [Abstract] [Full Text] [PDF]
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J. Chehimi, Q. Luo, L. Azzoni, L. Shawver, N. Ngoubilly, R. June, G. Jerandi, M. Farabaugh, and L. J. Montaner HIV-1 transmission and cytokine-induced expression of DC-SIGN in human monocyte-derived macrophages J. Leukoc. Biol., November 1, 2003; 74(5): 757 - 763. [Abstract] [Full Text] [PDF]
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J. A. Willment, H.-H. Lin, D. M. Reid, P. R. Taylor, D. L. Williams, S. Y. C. Wong, S. Gordon, and G. D. Brown Dectin-1 Expression and Function Are Enhanced on Alternatively Activated and GM-CSF-Treated Macrophages and Are Negatively Regulated by IL-10, Dexamethasone, and Lipopolysaccharide J. Immunol., November 1, 2003; 171(9): 4569 - 4573. [Abstract] [Full Text] [PDF]
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 L. Gardner and A. Moffett Dendritic Cells in the Human Decidua Biol Reprod, October 1, 2003; 69(4): 1438 - 1446. [Abstract] [Full Text] [PDF]
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A. K. De, K. Laudanski, and C. L. Miller-Graziano Failure of Monocytes of Trauma Patients to Convert to Immature Dendritic Cells is Related to Preferential Macrophage-Colony-Stimulating Factor-Driven Macrophage Differentiation J. Immunol., June 15, 2003; 170(12): 6355 - 6362. [Abstract] [Full Text] [PDF]
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A. Puig-Kroger, O. Muniz-Pello, R. Selgas, G. Criado, M-A. Bajo, J. A. Sanchez-Tomero, V. Alvarez, G. del Peso, P. Sanchez-Mateos, C. Holmes, et al. Peritoneal dialysis solutions inhibit the differentiation and maturation of human monocyte-derived dendritic cells: effect of lactate and glucose-degradation products J. Leukoc. Biol., April 1, 2003; 73(4): 482 - 492. [Abstract] [Full Text] [PDF]
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 L. Tailleux, O. Schwartz, J.-L. Herrmann, E. Pivert, M. Jackson, A. Amara, L. Legres, D. Dreher, L. P. Nicod, J. C. Gluckman, et al. DC-SIGN Is the Major Mycobacterium tuberculosis Receptor on Human Dendritic Cells J. Exp. Med., January 6, 2003; 197(1): 121 - 127. [Abstract] [Full Text] [PDF]
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E. J. Ryan, A. J. Marshall, D. Magaletti, H. Floyd, K. E. Draves, N. E. Olson, and E. A. Clark Dendritic Cell-Associated Lectin-1: A Novel Dendritic Cell-Associated, C-Type Lectin-Like Molecule Enhances T Cell Secretion of IL-4 J. Immunol., November 15, 2002; 169(10): 5638 - 5648. [Abstract] [Full Text] [PDF]
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M. Colmenares, A. Puig-Kroger, O. M. Pello, A. L. Corbi, and L. Rivas Dendritic Cell (DC)-specific Intercellular Adhesion Molecule 3 (ICAM-3)-grabbing Nonintegrin (DC-SIGN, CD209), a C-type Surface Lectin in Human DCs, Is a Receptor for Leishmania Amastigotes J. Biol. Chem., September 20, 2002; 277(39): 36766 - 36769. [Abstract] [Full Text] [PDF]
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C. P. Alvarez, F. Lasala, J. Carrillo, O. Muniz, A. L. Corbi, and R. Delgado C-Type Lectins DC-SIGN and L-SIGN Mediate Cellular Entry by Ebola Virus in cis and in trans J. Virol., June 5, 2002; 76(13): 6841 - 6844. [Abstract] [Full Text] [PDF]
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 I. Melero, I. Gabari, A. L. Corbi, M. Relloso, G. Mazzolini, V. Schmitz, M. Rodriguez-Calvillo, I. Tirapu, E. Camafeita, J. P. Albar, et al. An Anti-ICAM-2 (CD102) Monoclonal Antibody Induces Immune-mediated Regressions of Transplanted ICAM-2-negative Colon Carcinomas Cancer Res., June 1, 2002; 62(11): 3167 - 3174. [Abstract] [Full Text] [PDF]
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