|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
IMMUNOBIOLOGY
From Centro de Investigaciones Biológicas,
Consejo Superior de Investigaciones Científicas; and
Departamento de Biología Animal y Genética, Facultad de
Ciencias, Universidad del Pais Vasco, Madrid, Spain.
Dendritic cells (DC) are highly specialized antigen-presenting
cells that on activation by inflammatory stimuli (eg, tumor necrosis
factor Dendritic cells (DC) are professional
antigen-presenting cells that are critically involved in the initiation
of T cell-dependent immune responses as a consequence of their high
expression of major histocompatibility complex (MHC) and costimulatory
molecules.1 DC are sparsely distributed throughout the
body and, in most tissues, are present in an immature state, showing a
high capacity for antigen uptake and processing but unable to stimulate
T cells.1,2 Once activated by inflammatory stimuli or
infectious agents, DC undergo a maturation process whose hallmarks are
up-regulated expression of costimulatory (CD40, CD80, and CD86) and
adhesion (CD54 and CD58) molecules, migration into lymphoid organs, and subsequent acquisition of the capacity to activate quiescent, naïve, and memory lymphocytes.1-4 In vitro, DC can
be derived from either precursor cells or peripheral blood
monocytes5-8 when the appropriate cytokine signals are
provided. Immature monocyte-derived DC (MDDC) can be obtained from
peripheral blood monocytes in the presence of granulocyte-macrophage
colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Addition
of lipopolysaccharide (LPS) or tumor necrosis factor At least 3 distinct mitogen-activated protein kinase (MAPK) signaling
cascades exist in mammals, including the extracellular signal-regulated
kinase (ERK), the c-Jun N-terminal kinase (JNK), and the p38 MAPK
pathways.12 These kinases are activated by phosphorylation
by distinct upstream MAPK kinases. The ERK signaling cascade regulates
cell proliferation and differentiation in response to mitogens and
growth factors, whereas the JNK and p38 MAPK pathways are
preferentially activated by stress-inducing agents.12 The availability of specific inhibitors for the ERK and p38 MAPK pathways allows evaluation of their respective involvement in cellular responses
to extracellular stimuli. The ERK pathway inhibitors PD9805913 and U012614 prevent activation of
mitogen-activated protein kinase kinase (MEK) 1/2,15
upstream activators of ERK 1/2, whereas the pyridinyl imidazole
SB203580 inhibits p38 MAPK activity.15,16
The intracellular signaling pathways implicated in maturation of MDDC
are just beginning to be explored. TNF- In this study, we found that the ERK signaling pathway regulates
maturation of MDDC, since acquisition of phenotypic and functional maturation markers was enhanced in the presence of the MEK 1/2 inhibitors PD98059 and U0126. Together, our results indicate that the
ERK and p38 MAPK signaling pathways exert opposite effects on the
maturation of DC, thereby suggesting that maturation of MDDC can be
pharmacologically modified by altering the relative levels of
activation of both intracellular signaling routes.
Cytokines, enzyme-linked immunosorbent assay, and reagents
Cells
Flow cytometry and antibodies Cellular phenotypic analysis was done by using indirect immunofluorescence. The mAbs used for cell-surface staining included T3b (anti-CD3), TS1/2 (anti-MHC class II), HP2/1, and ALC1/6.3 (anti-CD49d) (kindly provided by Dr F. Sánchez-Madrid, Hospital Universitario de La Princesa, Madrid, Spain); HB1/5 (anti-CD83; Immunotech, Marseille, France); B-T7 (anti-CD86; Diaclone Research); and B-B20 (anti-CD40; Diaclone Research). All incubations were done in the presence of 50 µg/mL human IgG to prevent binding through the Fc portion of the antibodies. The supernatant from the myeloma P3 (X63) cell line was always included as a negative control. Flow cytometry analysis was done with an EPICS-CS instrument (Coulter Científica, Madrid, Spain) using log amplifiers. Where indicated, results are expressed as an expression index calculated as the percentage of marker-positive cells multiplied by their mean fluorescence intensity (MFI).Northern blotting After extensive washing in PBS, cells were harvested, and total cellular RNA was isolated by using RNeasy columns (Qiagen, Hilden, Germany) according to the manufacturer's recommendations. RNA integrity was initially confirmed in agarose gels containing formaldehyde. Denatured RNA (10 µg) was size fractionated on formaldehyde-containing 1% agarose gels in the presence of ethidium bromide. After electrophoresis, RNA was transferred overnight to nitrocellulose membranes with 20 × standard saline citrate (SSC). Prehybridization was done overnight at 42°C in 50% formamide, 5 × SSC, 5 × Denhardt solution, 50 mM sodium phosphate (pH 6.5), and 250 µg/mL denatured salmon-sperm DNA. Membranes were hybridized for 16 hours at 42°C in the same solution but containing 106 cpm/mL oligo-labeled probe. Blots were washed sequentially in 2 × SSC, 0.5% sodium dodecyl sulfate (SDS) at room temperature and then in 0.3 × SSC, 0.5% SDS at 65°C and exposed to x-ray film at 70°C. Detection of CD49d messenger RNA (mRNA) was
accomplished with a 1.8-kilobase-pair EcoRI fragment of the
CD49d complementary DNA (cDNA).24 For detection of CD83
mRNA, full-length CD83 cDNA was obtained by polymerase chain reaction
using oligonucleotides 5'-GGGAATTCGCGCTCCAGCCATGTCGCGC-3' and
5'-CCCCAAGCTTCCTGCAGAAATCCTGCTCATACC-3' as primers. For this procedure,
2 µg total RNA from mature MDDC was reverse transcribed in a total
volume of 20 µL amplification buffer (50 mM Tris-hydrochloric acid
[HCl] [pH 8.2], 5 mM magnesium chloride, 10 mM dithiothreitol
[DTT], 50 mM potassium chloride, 1 mM of each deoxynucleotide, and
0.5 µM random hexamers) including RNAsin and avian myeloblastosis
virus reverse transcriptase at a concentration of 1 U/µL. The mixture
was incubated at 42°C for 60 minutes and then at 52°C for 30 minutes, and the final volume was increased to 100 µL with water.
Amplification of the full-length CD83 mRNA was done on 5 µL of each
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
Pfu DNA polymerase (Stratagene, La Jolla, CA). Using a
similar approach, we employed oligonucleotides
5'-GATGTGTCACCAGCAGTTGG-3' and 5'-CTAACTGCAGGGCACAGATG-3' to amplify
the whole coding sequence of IL-12 p40 from total RNA of
mature MDDC.
Measurement of phagocytic activity of MDDC Mannose-receptor-mediated endocytosis was measured after 48 hours of maturation. Mature MDDC (5 × 105 cells/mL) were incubated in a 200-µL solution buffered with 25 mM HEPES with 1 mg/mL fluorescein isothiocyanate-dextran (Sigma). After a 1-hour incubation at 37°C, cells were washed 4 times in ice-cold PBS and analyzed with an EPICS flow cytometer (Coulter Científica). For a control, cells from each culture condition were also maintained in the same solution for 1 hour at 4°C.Allogeneic T-lymphocyte proliferation induced by MDDC Allogeneic T lymphocytes were obtained from peripheral blood samples from healthy adults by using standard procedures. CD4+ T lymphocytes were isolated from umbilical cord blood by immunomagnetic positive selection using CD4 mAb-conjugated beads (Dynal, Oslo, Norway). For T-lymphocyte proliferation experiments, 2 × 105 T cells were stimulated in a 96-well plate with 0.2 × 10,3 0.4 × 10,3 10,3 2 × 103, or 5 × 103 irradiated (1.5 Gy/min for 10 minutes) allogeneic MDDC matured under the different culture conditions. After a 5-day incubation period, tritium-thymidine was added (0.037 MBq/well) during the last 16 hours of coculture and thymidine incorporation determined to assess the level of T-cell proliferation.Western blotting Total cell lysates were obtained in 50 mM HEPES [pH 7.5], 250 mM sodium chloride (NaCl), 1 mM EDTA, 0.5% Triton X-100, 0.5 mM DTT, 10 mM sodium fluoride, 1 mM sodium orthovanadate, 20 mM Pefabloc, and 2 µg/mL aprotinin, antipain, leupeptin, and pepstatin. Then, 10 µg of each lysate were subjected to SDS-polyacrylamide gel electrophoresis under reducing conditions and transferred to an Immobilon polyvinylidene difluoride membrane (Millipore, Bedford, MA). After blocking of the unoccupied sites with 5% bovine serum albumin in 50 mM Tris-HCl (pH 7.6), 150 mM NaCl, and 0.1% Tween-20, protein detection was done with a chemiluminescence system (Supersignal West Pico; Pierce, Rockford, IL). For reprobing, membranes were incubated in stripping buffer (62.5 mM Tris-HCl [pH 6.7], 100 mM -mercaptoethanol, and 2% SDS) for 30 minutes at 50°C, with
occasional agitation. Detection of ERK 1/2, p38, phospho-ERK 1/2,
phospho-p38, and I B was done by using specific polyclonal
antibodies (New England Biolabs, Beverly, MA, and Santa Cruz
Biotechnology, Santa Cruz, CA).
Electrophoretic mobility shift assay Electrophoretic mobility shift assay (EMSA) was done essentially as described previously,25 and nuclear extracts were prepared according to the method described Schreiber et al.26 For competition experiments, unlabeled oligonucleotides (100-fold molar excess) were preincubated with the nuclear extracts at 4°C for 30 minutes before the probe was added. Oligonucleotide probes were nuclear factorB (NF-B)
consensus 5'-AGTTGAGGGGACTTTCCCAGGC-3', AP1 consensus
5'-CGCTTGATGAGTCAGCCGGAA-3', and CAAT enhancer-binding protein (C/EBP)
consensus 5'-TGCAGATTGCGCAATCTGCA-3', which contain consensus-binding
sites for NF-B, AP-1, and C/EBP, respectively.
Serum has a negative regulatory effect on maturation of MDDC During studies analyzing TNF--induced maturation of MDDC, we
noticed that acquisition of the maturation marker CD83 was delayed in
the presence of serum compared with maturation accomplished in
serum-free medium (Figure 1A), a finding
in agreement with previously reported results.27 The
inhibitory effect of serum, reflected in both the percentage of
CD83+ cells and the CD83 MFI of the whole population of
MDDC, was obvious at 24 hours and still evident after 48 hours of
treatment with TNF- (Figure 1A). To determine which
signal-transduction pathway might be mediating the serum inhibitory
effect, maturation of MDDC was done with serum and in the presence of
the MEK 1/2 inhibitor U0126, which inhibits activation of the MEK
1/2-ERK MAPK pathway. TNF--induced expression of CD83 was
augmented in the presence of U0126 at both 24 and 48 hours, reaching
levels similar to those obtained in the absence of serum (Figure 1A).
Similar enhancing effects were observed when maturation took place in
the presence of PD98059,13 an alternative inhibitor of the
ERK signaling pathway (data not shown). Conversely, and as previously
described,10,18,23 the p38 MAPK inhibitor SB203580 greatly
impaired acquisition of the CD83 maturation marker (Figure
2). These results suggest that serum
delays maturation of MDDC by activating the ERK signal-transduction pathway. To control the specificity of the inhibitors, activation of
ERK and p38 MAPK was assessed by Western blot analysis. As expected,
ERK pathway inhibitors abolished TNF--induced ERK phosphorylation (Figure 1B). Conversely, SB203580 significantly prevented
TNF--induced phosphorylation of p38 MAPK (Figure 1B). Together,
these results suggest that activation of the ERK signaling pathway has
an inhibitory role in the maturation of MDDC.
Phenotypic maturation of MDDC is differentially influenced by the ERK and p38 MAPK signaling pathways: effects on maturation markers and costimulatory molecules To assess the influence of the p38 MAPK and ERK signaling pathways on maturation of MDDC, all subsequent experiments were done in the presence of serum, and TNF--induced maturation was carried out in
the presence of inhibitors of one of the signaling routes.
Maturation of MDDC in the presence of PD98059 resulted in greater
expression of the maturation markers CD83 and CD49d (Figure 2A).
Moreover, PD98059 markedly increased up-regulation of CD86 and slightly
enhanced the maturation-dependent up-regulation of MHC class II
molecules but did not affect expression of CD40 or CD11c (Figure 2B-C).
All these effects of PD98059 were observed 48 hours after TNF- was
added, although some were seen as early as 24 hours into the
maturation process (CD83 in Figure 2A). The inhibitory role of
the ERK signal-transduction pathway on phenotypic maturation of MDDC
was also indicated by studies using U0126, since this inhibitor also
increased expression of CD83, CD49d, and CD86 without affecting
expression of CD40 and CD11c (Figure 1A and data not shown).
Conversely, the p38 MAPK inhibitor SB203580 blocked TNF--induced
up-regulation of the maturation markers CD83 and CD49d on MDDC (Figure
2A-B). SB203580 also reduced up-regulation of the costimulatory
molecule CD86 and that of MHC class II, but expression of other
cell-surface molecules (CD40) was not affected or was even slightly
increased (CD11c; Figure 2B-C). No effect on the normal
maturation pathway was observed when either PD98059, U0126, or SB203580
was used alone, and the PD98059 enhancing effect was observed at
TNF- concentrations between 2 ng/mL and 600 ng/mL (data not shown).
Therefore, PD98059 and U0126 increased TNF--induced up-regulation
of maturation markers (CD83 and CD49d) and costimulatory molecules
(CD86), whereas SB203580 inhibited their expression, suggesting that
the ERK and p38 MAPK signaling pathways have opposite effects on the
phenotypic maturation of MDDC.
To further analyze the influence of PD98059 and SB203580 on expression
of markers of maturation of MDDC, levels of CD83, CD49d, and IL-12 p40
mRNA were determined during TNF-
Functional maturation of MDDC is differentially influenced by ERK and p38 MAPK pathway inhibitors Immature DC capture and process antigens as a consequence of their high endocytic activity, a feature that is lost during maturation.2,29 Compared with immature MDDC, TNF--treated cells had a reduced level of mannose-receptor
endocytosis (Figure 4). Treatment with
PD98059 before the maturation stimulus further increased the loss of
endocytic activity during TNF--induced maturation (Figure 4).
Conversely, no significant change in endocytic activity was observed
after 48 hours of maturation in the presence of the p38 MAPK inhibitor
SB203580 (Figure 4). These results indicate that blockade of the
MAPK-ERK pathway not only potentiates phenotypic maturation but also
enhances loss of mannose-receptor-mediated endocytic
activity.
After exposure to maturation stimuli, MDDC produce numerous chemokines
and cytokines, including TNF-
The differential inhibitory effect of PD98059 at 24 and 48 hours after
LPS maturation suggested that inhibition of the ERK signaling pathway
may affect the kinetics of IL-12 release. Because of this and because
IL-12 p70 is not produced in response to TNF- Because p38 MAPK and ERK pathway inhibitors had differential effects on
phenotypic maturation of MDDC, and especially on expression of
molecules critical for naive T-lymphocyte stimulation, we assessed the
effects of the inhibitors on the T-cell response induced by allogeneic
MDDC. As expected, MDDC stimulated with TNF-
On the other hand, SB203580 pretreatment impaired acquisition of T-cell
stimulatory activity by mature MDDC, although its effects were more
evident when LPS was used as a maturation agent (Figure 6A-B). The
effects of the ERK pathway inhibitors on T-cell activation mediated by
MDDC were also evaluated by using CD4+ cord-blood T cells,
which contain a higher proportion of naive CD45RA+
lymphocytes.31 As shown in Figure 6C, U0126 pretreatment
increased the T-cell stimulatory ability of LPS-matured MDDC by 90%
(24 030 ± 3626 versus 44 207 ± 5122), whereas
SB203580 inhibited the T-cell response. The enhancing effect of U0126
was also observed at stimulator:responder ratios of 1:40 (8321 ± 1214 versus 20 310 ± 3116) and 1:200 (1024 ± 118 versus 2709 ± 723; Figure 6C). Together, these results
indicate that PD98059 potentiates and SB203580 represses the
TNF- The ERK signal-transduction pathway negatively regulates NF- B transcription-factor family members, especially RelB, are
essential for maturation of DC.32 As shown in Figure
7A, we found, in agreement with previous
studies,33,34 that the DNA-binding activity of NF-B
increased during maturation of MDDC, concomitantly with a decrease in
the DNA-binding activity of C/EBP and AP-1. Inhibition of ERK
activation before LPS-induced or TNF--induced maturation caused a
further increase in NF-B measured either 24 or 48 hours after the
maturation agent was added (Figure 7B). Similar effects were obtained
by using the PD98059 ERK pathway inhibitor (data not shown), thus
providing additional evidence that maturation of MDDC was enhanced by
blockade of the ERK signaling pathway before addition of the
maturation-inducing agents. Conversely, SB203580 inhibited the increase
in NF-B DNA-binding activity induced by either LPS or TNF-
(Figure 7B). On the other hand, it was previously shown that levels of
IB and Bcl-3 increase during maturation of MDDC.34
Therefore, immunoblotting of cytoplasmic proteins was done to determine
the relative levels of IB under the different experimental
conditions. As expected, IB levels increased when measured 24 hours after TNF--induced maturation (Figure
8). Moreover, IB levels increased
further in MDDC matured in the presence of PD98059 after 24 and 48 hours, whereas SB203580 caused a reduction in the levels of IB
with respect to those observed in MDDC matured with TNF- alone
(Figure 8). Therefore, ERK signaling-pathway inhibitors
potentiate the increase in NF-B and IB that takes place during
maturation of MDDC.
After DC are exposed to inflammatory stimuli or bacterial
products, they undergo functional maturation and reenter the
circulatory system to home to the T-cell areas of the draining lymphoid
organs.2,29 In this study, we assessed the effects of the
ERK signaling pathway on the phenotypic and functional maturation of
MDDC in response to either TNF- The opposing roles of the ERK and p38 MAPK pathways in the maturation
of DC are evocative of events in other cellular differentiation systems. During cartilage formation, p38 MAPK and ERK 1/2 act as
positive and negative regulators of chondrogenesis by conversely regulating expression of different adhesion molecules, including N-cadherin, fibronectin, and the CD49e/CD29 integrin.35
Similarly, butyrate-induced erythroid differentiation of K562 cells was
found to be distinctly modulated by inhibition of either ERK 1/2 or p38
MAPK activity.36 In both cases, cell differentiation was promoted through the p38 MAPK signal-transduction pathway whereas ERK
activation was a negative regulator.35,36 A similar
mechanism appears to be present in MDDC. The molecular mechanism by
which ERK negatively regulates maturation of MDDC is unknown. However, it has been proposed that a constitutive active MEK-ERK pathway is
capable of negatively regulating NF- Unlike the results with SB203580, maturation of MDDC in the presence of
MEK 1/2 inhibitors resulted in augmented expression of MHC class II,
costimulatory, and adhesion molecules; faster induction of CD83;
increased NF- The final outcome of maturation of DC depends on the maturation stimulus and the environmental signals received by DC on activation.40,41 Three functional subsets of DC might be generated: a subset with high costimulatory capacity and IL-12 production (DC1), a subset with high costimulatory capacity but low IL-12 production (DC2), and a subset with low costimulatory capacity and IL-12 production (DC3).40 According to this model, DC1 would promote Th1 polarization, whereas DC2 would drive Th2 differentiation and type 3 would give rise to tolerogenic Th lymphocytes.40 Our results with MDDC indicate that the type of T-cell polarizing activity shown by these cells might depend on the balance between ERK and p38 MAPK activation triggered by maturation stimuli and environmental signals. In this manner, maturation of MDDC in an extracellular context favoring a low ratio of ERK to p38 MAPK activation would give rise to DC with Th1-polarizing capacity, whereas a high ratio would shift the process toward a Th2-tolerogenic outcome. Moreover, it was proposed that the polarizing capacity of DC is determined by the kinetics of activation30: the "DC exhaustion model" proposes that MDDC promote Th1 polarization at the early stages of maturation (active DC) and induce Th2 differentiation once their IL-12 production ability has diminished (exhausted DC). If this model is accurate, it may be that ERK inhibitors accelerate the kinetics of maturation of MDDC and reduce the time frame before exhaustion. We are currently testing this hypothesis by determining the relative proportion of antigen-specific Th1 and Th2 lymphocytes generated by MDDC matured in the presence of ERK or p38 MAPK inhibitors.
We thank Dr Pedro Lastres for flow cytometry and Alba Galán, Patricio Aller, and Jorge Martín for helpful discussions and for sharing reagents.
Submitted January 18, 2001; accepted June 14, 2001.
Supported by grants SAF98/0068 from Comisión Interministerial de Ciencia y Tecnología, 08.3/0026/2000.1 from Comunidad Autónoma de Madrid and Fondo de Investigación Sanitaria 01/0063-01 (A.L.C.), and SAF2000/0132 (C.B.). A.P.-K. is the recipient of a fellowship from Instituto Reina Sofía (Fundación Renal Iñigo Alvarez de Toledo).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Angel L. Corbí, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Velázquez 144, 28006 Madrid, Spain: e-mail: acorbi{at}cib.csic.es.
1.
Hart DNJ.
Dendritic cells: unique leukocyte populations which control the primary immune response.
Blood.
1997;90:3245-3287 2. Banchereau J, Steinman RM. Dendritic cells and the control of the immunity. Nature. 1998;392:245-252[CrossRef][Medline] [Order article via Infotrieve]. 3. Steinman RM, Inaba K. Myeloid dendritic cells. J Leuk Biol. 1999;66:205-208[Abstract]. 4. Cella M, Sallusto F, Lanzavecchia A. Origin, maturation and antigen presenting function of dendritic cells. Curr Opin Immunol. 1997;9:10-16[CrossRef][Medline] [Order article via Infotrieve].
5.
Sallusto A, Lanzavecchia A.
Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor 6. Romani N, Reider D, Heuer M, et al. Generation of mature dendritic cells from human blood. An improved method with special regard to clinical applicability. J Immunol Methods. 1996;196:137-151[CrossRef][Medline] [Order article via Infotrieve]. 7. Bender A, Sapp M, Schuler G, Steinman RM, Bhardwaj N. Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood. J Immunol Methods. 1996;196:121-135[CrossRef][Medline] [Order article via Infotrieve].
8.
Caux C, Vanbervliet B, Massacrier C, et al.
CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF + TNF-
9.
Zhou LJ, Tedder TF.
CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells.
Proc Natl Acad Sci U S A.
1996;93:2588-2592
10.
Puig-Kröger A, Sanz-Rodríguez F, Longo P, et al.
Maturation-dependent expression and function of the CD49d integrin on monocyte-derived human dendritic cells.
J Immunol.
2000;165:4338-4345
11.
Shortman K, Caux C.
Dendritic cell development: multiple pathways to nature's adjuvant.
Stem Cells.
1997;15:409-419 12. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410:37-40[CrossRef][Medline] [Order article via Infotrieve].
13.
Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR.
A synthetic inhibitor of the mitogen-activated protein kinase cascade.
Proc Natl Acad Sci U S A.
1995;92:7686-7689
14.
Favata MF, Horiuchi KY, Manos EJ, et al.
Identification of a novel inhibitor of mitogen-activated protein kinase kinase.
J Biol Chem.
1998;273:18623-18632 15. Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000;351:95-105[CrossRef][Medline] [Order article via Infotrieve]. 16. Cuenda A, Rouse J, Doza YN, et al. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 1995;364:229-233[CrossRef][Medline] [Order article via Infotrieve].
17.
Sato K, Nagayama H, Tadokoro K, Juji T, Takahashi TA.
Extracellular signal-regulated kinase, stress-activated protein kinase/c-Jun N-terminal kinase, and p38MAPK are involved in IL-10-mediated selective repression of TNF-
18.
Arrighi J-F, Rebsamen M, Rousset F, Kindler V, Hauser C.
A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF- 19. Lu H-T, Yang DD, Wysk M, et al. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J. 1999;18:1845-1857[CrossRef][Medline] [Order article via Infotrieve].
20.
Fukao T, Matsuda S, Koyasu S.
Synergistic effects of IL-4 and IL-18 on IL-12-dependent IFN- 21. Häcker H, Mischak H, Miethke T, et al. CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. EMBO J. 1998;17:6230-6240[CrossRef][Medline] [Order article via Infotrieve].
22.
Aicher A, Shu GL, Magaletti D, et al.
Differential role for p38 mitogen-activated protein kinase in regulating CD40-induced gene expression in dendritic cells.
J Immunol.
1999;163:5786-5795
23.
Ardeshna KM, Pizzey AR, Devereux S, Khwaja A.
The PI3 kinase, p38 SAP kinase, and NF-
24.
Takada Y, Elices MJ, Crouse C, Hemler ME.
The primary structure of the 25. Lopez-Rodriguez C, Zubiaur M, Sancho J, Concha A, Corbi AL. An octamer element functions as a regulatory element in the differentiation-responsive CD11c integrin gene promoter: OCT-2 inducibility during myelomonocytic differentiation. J Immunol. 1997;158:5833-5840[Abstract].
26.
Schreiber EP, Matthias P, Müller MM, Schaffner W.
Rapid detection of octamer binding proteins with `mini-extracts', prepared from a small number of cells.
Nucleic Acids Res.
1989;17:6419
27.
Lyakh LA, Koski GK, Telford W, Gress RE, Cohen PA, Rice NR.
Bacterial lipopolysaccharide, TNF- 28. Häcker H, Mischak H, Häcker G, et al. Cell type-specific activation of mitogen-activated protein kinases by CpG-DNA controls interleukin-12 release from antigen-presenting cells. EMBO J. 1999;18:6973-6982[CrossRef][Medline] [Order article via Infotrieve]. 29. Bell D, Young JW, Banchereau J. Dendritic cells. Adv Immunol. 1999;72:255-324[Medline] [Order article via Infotrieve]. 30. Langenkamp A, Mesi M, Lanzavecchia A, Sallusto F. Kinetics of dendritic cell activation: impact on priming of Th1, Th2 and nonpolarized T cells. Nature Immunol. 2000;1:311-316[CrossRef][Medline] [Order article via Infotrieve]. 31. Hannet I, Erkeller-Yuksel F, Lydyard P, Deneys V, DeBruyére M. Developmental and maturational changes in human blood lymphocyte subpopulations. Immunol Today. 1992;13:215-218[CrossRef][Medline] [Order article via Infotrieve].
32.
Wu L, D'Amico A, Winkel KD, Suter M, Lo D, Shortman K.
RelB is essential for the development of myeloid-related CD8
33.
Verhasselt V, Vanden Berghe W, Vanderheyde N, et al.
N-acetyl-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-
34.
Neumann M, Fries H-W, Scheicher C, et al.
Differential expression of Rel/NF-
35.
Oh C-D, Chang S-H, Yoon Y-M, et al.
Opposing role of mitogen-activated protein kinase subtypes, erk-1/2 and p38, in the regulation of chondrogenesis of mesenchymes.
J Biol Chem.
2000;275:5613-5619
36.
Witt O, Sand K, Pekrun A.
Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways.
Blood.
2000;95:2391-2396
37.
Carter AB, Hunninghake GW.
A constitutive active MEK-ERK pathway negatively regulates NF-
38.
Murphy TL, Cleveland MG, Kulesza P, Magram J, Murphy KM.
Regulation of interleukin 12 p40 expression through an NF-
39.
Baeuerle PA, Henkel T.
Function and activation of NF- 40. Kalinski P, Hilkens CMU, Wierenga EA, Kapsenberg ML. T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal. Immunol Today. 1999;20:561-567[CrossRef][Medline] [Order article via Infotrieve].
41.
Vieira PL, de Jong EC, Wierenga EA, Kapsenberg ML, Kalinski P.
Development of Th1-inducing capacity in myeloid dendritic cells requires environmental instruction.
J Immunol.
2000;164:4507-4512
© 2001 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  S. M. Makela, M. Strengell, T. E. Pietila, P. Osterlund, and I. Julkunen Multiple signaling pathways contribute to synergistic TLR ligand-dependent cytokine gene expression in human monocyte-derived macrophages and dendritic cells J. Leukoc. Biol., April 1, 2009; 85(4): 664 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Stephens, E. Nikoopour, B. J. Rider, M. Leon-Ponte, T. A. Chau, S. Mikolajczak, P. Chaturvedi, E. Lee-Chan, R. A. Flavell, S. M. M. Haeryfar, et al. Dendritic Cell Differentiation Induced by a Self-Peptide Derived from Apolipoprotein E J. Immunol., November 15, 2008; 181(10): 6859 - 6871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ohtani, S. Nagai, S. Kondo, S. Mizuno, K. Nakamura, M. Tanabe, T. Takeuchi, S. Matsuda, and S. Koyasu Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells Blood, August 1, 2008; 112(3): 635 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Mukherjee and V. S. Chauhan Plasmodium falciparum-free merozoites and infected RBCs distinctly affect soluble CD40 ligand-mediated maturation of immature monocyte-derived dendritic cells J. Leukoc. Biol., July 1, 2008; 84(1): 244 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Valentinis, A. Capobianco, F. Esposito, A. Bianchi, P. Rovere-Querini, A. A. Manfredi, and C. Traversari Human recombinant heat shock protein 70 affects the maturation pathways of dendritic cells in vitro and has an in vivo adjuvant activity J. Leukoc. Biol., July 1, 2008; 84(1): 199 - 206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Hipp, N. Hilf, S. Walter, D. Werth, K. M. Brauer, M. P. Radsak, T. Weinschenk, H. Singh-Jasuja, and P. Brossart Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses Blood, June 15, 2008; 111(12): 5610 - 5620. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Liang, C. Workman, J. Lee, C. Chew, B. M. Dale, L. Colonna, M. Flores, N. Li, E. Schweighoffer, S. Greenberg, et al. Regulatory T Cells Inhibit Dendritic Cells by Lymphocyte Activation Gene-3 Engagement of MHC Class II J. Immunol., May 1, 2008; 180(9): 5916 - 5926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Jiang, G. Chen, Y. Zhang, L. Lu, S. Liu, and X. Cao Nerve Growth Factor Promotes TLR4 Signaling-Induced Maturation of Human Dendritic Cells In Vitro through Inducible p75NTR 1 J. Immunol., November 1, 2007; 179(9): 6297 - 6304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Li, S. Abediankenari, Y.-J. Kim, T. B. Campbell, S. Ito, B. Graham-Evans, S. Cooper, and H. E. Broxmeyer TGF-{beta} combined with M-CSF and IL-4 induces generation of immune inhibitory cord blood dendritic cells capable of enhancing cytokine-induced ex vivo expansion of myeloid progenitors Blood, October 15, 2007; 110(8): 2872 - 2879. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Handley, J. Rasaiyaah, J. Barnett, M. Thakker, G. Pollara, D. R. Katz, and B. M. Chain Expression and function of mixed lineage kinases in dendritic cells Int. Immunol., August 13, 2007; (2007) dxm050v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Li, S. Basu, M.-K. Han, Y.-J. Kim, and H. E. Broxmeyer Influence of ERK activation on decreased chemotaxis of mature human cord blood monocyte-derived dendritic cells to CCL19 and CXCL12 Blood, April 15, 2007; 109(8): 3173 - 3176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. R. Karaolis, T. K. Means, D. Yang, M. Takahashi, T. Yoshimura, E. Muraille, D. Philpott, J. T. Schroeder, M. Hyodo, Y. Hayakawa, et al. Bacterial c-di-GMP Is an Immunostimulatory Molecule J. Immunol., February 15, 2007; 178(4): 2171 - 2181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Agaugue, L. Perrin-Cocon, F. Coutant, P. Andre, and V. Lotteau 1-Methyl-Tryptophan Can Interfere with TLR Signaling in Dendritic Cells Independently of IDO Activity J. Immunol., August 15, 2006; 177(4): 2061 - 2071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Luft, E. Rodionova, E. Maraskovsky, M. Kirsch, M. Hess, C. Buchholtz, M. Goerner, M. Schnurr, R. Skoda, and A. D. Ho Adaptive functional differentiation of dendritic cells: integrating the network of extra- and intracellular signals Blood, June 15, 2006; 107(12): 4763 - 4769. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Macagno, M. Molteni, A. Rinaldi, F. Bertoni, A. Lanzavecchia, C. Rossetti, and F. Sallusto A cyanobacterial LPS antagonist prevents endotoxin shock and blocks sustained TLR4 stimulation required for cytokine expression J. Exp. Med., June 12, 2006; 203(6): 1481 - 1492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Agrawal, S. Dillon, T. L. Denning, and B. Pulendran ERK1-/- Mice Exhibit Th1 Cell Polarization and Increased Susceptibility to Experimental Autoimmune Encephalomyelitis J. Immunol., May 15, 2006; 176(10): 5788 - 5796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. Yasutomi, Y. Ohshima, N. Omata, A. Yamada, H. Iwasaki, Y. Urasaki, and M. Mayumi Erythromycin Differentially Inhibits Lipopolysaccharide- or Poly(I:C)-Induced but Not Peptidoglycan-Induced Activation of Human Monocyte-Derived Dendritic Cells J. Immunol., December 15, 2005; 175(12): 8069 - 8076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Palova-Jelinkova, D. Rozkova, B. Pecharova, J. Bartova, A. Sediva, H. Tlaskalova-Hogenova, R. Spisek, and L. Tuckova Gliadin Fragments Induce Phenotypic and Functional Maturation of Human Dendritic Cells J. Immunol., November 15, 2005; 175(10): 7038 - 7045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Loscher, E. Draper, O. Leavy, D. Kelleher, K. H. G. Mills, and H. M. Roche Conjugated Linoleic Acid Suppresses NF-{kappa}B Activation and IL-12 Production in Dendritic Cells through ERK-Mediated IL-10 Induction J. Immunol., October 15, 2005; 175(8): 4990 - 4998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Iijima, Y. Yanagawa, J. M. Clingan, and K. Onoe CCR7-mediated c-Jun N-terminal kinase activation regulates cell migration in mature dendritic cells Int. Immunol., September 1, 2005; 17(9): 1201 - 1212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. K. Kang, H.-Y. Lee, M.-K. Kim, K. S. Park, Y. M. Park, J.-Y. Kwak, and Y.-S. Bae The Synthetic Peptide Trp-Lys-Tyr-Met-Val-D-Met Inhibits Human Monocyte-Derived Dendritic Cell Maturation via Formyl Peptide Receptor and Formyl Peptide Receptor-Like 2 J. Immunol., July 15, 2005; 175(2): 685 - 692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Valentinis, A. Bianchi, D. Zhou, A. Cipponi, F. Catalanotti, V. Russo, and C. Traversari Direct Effects of Polymyxin B on Human Dendritic Cells Maturation: THE ROLE OF I{kappa}B-{alpha}/NF-{kappa}B AND ERK1/2 PATHWAYS AND ADHESION J. Biol. Chem., April 8, 2005; 280(14): 14264 - 14271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Pekkari, M. T. Goodarzi, A. Scheynius, A. Holmgren, and J. Avila-Carino Truncated thioredoxin (Trx80) induces differentiation of human CD14+ monocytes into a novel cell type (TAMs) via activation of the MAP kinases p38, ERK, and JNK Blood, February 15, 2005; 105(4): 1598 - 1605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Wilflingseder, B. Mullauer, H. Schramek, Z. Banki, M. Pruenster, M. P. Dierich, and H. Stoiber HIV-1-Induced Migration of Monocyte-Derived Dendritic Cells Is Associated with Differential Activation of MAPK Pathways J. Immunol., December 15, 2004; 173(12): 7497 - 7505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nakahara, H. Uchi, K. Urabe, Q. Chen, M. Furue, and Y. Moroi Role of c-Jun N-terminal kinase on lipopolysaccharide induced maturation of human monocyte-derived dendritic cells Int. Immunol., December 1, 2004; 16(12): 1701 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Marteau, D. Communi, J.-M. Boeynaems, and N. Suarez Gonzalez Involvement of multiple P2Y receptors and signaling pathways in the action of adenine nucleotides diphosphates on human monocyte-derived dendritic cells J. Leukoc. Biol., October 1, 2004; 76(4): 796 - 803. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pollara, M. Jones, M. E. Handley, M. Rajpopat, A. Kwan, R. S. Coffin, G. Foster, B. Chain, and D. R. Katz Herpes Simplex Virus Type-1-Induced Activation of Myeloid Dendritic Cells: The Roles of Virus Cell Interaction and Paracrine Type I IFN Secretion J. Immunol., September 15, 2004; 173(6): 4108 - 4119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Chen, K. Doffek, S. L. Sugg, and J. Shilyansky Phosphatidylserine Regulates the Maturation of Human Dendritic Cells J. Immunol., September 1, 2004; 173(5): 2985 - 2994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Skinner, A. Reissinger, H. Shen, and M. H. Yuk Bordetella Type III Secretion and Adenylate Cyclase Toxin Synergize to Drive Dendritic Cells into a Semimature State J. Immunol., August 1, 2004; 173(3): 1934 - 1940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Duan, J. H. P. Chan, C. H. Wong, B. P. Leung, and W. S. F. Wong Anti-Inflammatory Effects of Mitogen-Activated Protein Kinase Kinase Inhibitor U0126 in an Asthma Mouse Model J. Immunol., June 1, 2004; 172(11): 7053 - 7059. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Tang, L. Liu, K. Kang, P. K. Mukherjee, M. Takahara, G. Chen, T. S. McCormick, K. D. Cooper, and M. Ghannoum Inhibition of Monocytic Interleukin-12 Production by Candida albicans via Selective Activation of ERK Mitogen-Activated Protein Kinase Infect. Immun., May 1, 2004; 72(5): 2513 - 2520. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Liu, H. Liu, B. O. Kim, V. H. Gattone, J. Li, A. Nath, J. Blum, and J. J. He CD4-Independent Infection of Astrocytes by Human Immunodeficiency Virus Type 1: Requirement for the Human Mannose Receptor J. Virol., April 15, 2004; 78(8): 4120 - 4133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Vermeulen, M. Giordano, A. S. Trevani, C. Sedlik, R. Gamberale, P. Fernandez-Calotti, G. Salamone, S. Raiden, J. Sanjurjo, and J. R. Geffner Acidosis Improves Uptake of Antigens and MHC Class I-Restricted Presentation by Dendritic Cells J. Immunol., March 1, 2004; 172(5): 3196 - 3204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Ma, K. Gee, W. Lim, K. Chambers, J. B. Angel, M. Kozlowski, and A. Kumar Dexamethasone Inhibits IL-12p40 Production in Lipopolysaccharide-Stimulated Human Monocytic Cells by Down-Regulating the Activity of c-Jun N-Terminal Kinase, the Activation Protein-1, and NF-{kappa}B Transcription Factors J. Immunol., January 1, 2004; 172(1): 318 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Franchi, I. Condo, B. Tomassini, C. Nicolo, and R. Testi A caspaselike activity is triggered by LPS and is required for survival of human dendritic cells Blood, October 15, 2003; 102(8): 2910 - 2915. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Matsuyama, M. Faure, and T. Yoshimura Activation of Discoidin Domain Receptor 1 Facilitates the Maturation of Human Monocyte-Derived Dendritic Cells Through the TNF Receptor Associated Factor 6/TGF-{beta}-Activated Protein Kinase 1 Binding Protein 1{beta}/p38{alpha} Mitogen-Activated Protein Kinase Signaling Cascade J. Immunol., October 1, 2003; 171(7): 3520 - 3532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Reed, B. Berwin, J. P. Baker, and C. V. Nicchitta GRP94/gp96 Elicits ERK Activation in Murine Macrophages: A ROLE FOR ENDOTOXIN CONTAMINATION IN NF-{kappa}B ACTIVATION AND NITRIC OXIDE PRODUCTION J. Biol. Chem., August 22, 2003; 278(34): 31853 - 31860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hewison, L. Freeman, S. V. Hughes, K. N. Evans, R. Bland, A. G. Eliopoulos, M. D. Kilby, P. A. H. Moss, and R. Chakraverty Differential Regulation of Vitamin D Receptor and Its Ligand in Human Monocyte-Derived Dendritic Cells J. Immunol., June 1, 2003; 170(11): 5382 - 5390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Gosset, F. Bureau, V. Angeli, M. Pichavant, C. Faveeuw, A.-B. Tonnel, and F. Trottein Prostaglandin D2 Affects the Maturation of Human Monocyte-Derived Dendritic Cells: Consequence on the Polarization of Naive Th Cells J. Immunol., May 15, 2003; 170(10): 4943 - 4952. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. G. Brinker, H. Garner, and J. R. Wright Surfactant protein A modulates the differentiation of murine bone marrow-derived dendritic cells Am J Physiol Lung Cell Mol Physiol, January 1, 2003; 284(1): L232 - L241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Relloso, A. Puig-Kroger, O. M. Pello, J. L. Rodriguez-Fernandez, G. de la Rosa, N. Longo, J. Navarro, M. A. Munoz-Fernandez, P. Sanchez-Mateos, and A. L. Corbi DC-SIGN (CD209) Expression Is IL-4 Dependent and Is Negatively Regulated by IFN, TGF-{beta}, and Anti-Inflammatory Agents J. Immunol., March 15, 2002; 168(6): 2634 - 2643. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
and given
the essential role of NF-
production by dendritic cells.
J Immunol.
2000;164:64-71
dendritic cells but not of lymphoid-related CD8