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Kali
ski2Academic Medical Center, Department of Cell Biology and Histology, University of Amsterdam, Amsterdam, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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induce mature DC, which can
secrete IL-12 and promote the development of Th0/Th1-biased cells. DC
maturation factors with a Th2-promoting function have not been
described. Here we show that PGE2, although it does not
induce final DC maturation by itself, synergizes with IL-1ß and
TNF-, and allows their effectiveness at 100-fold lower
concentrations. While being phenotypically identical with the DC
matured in the presence of high concentrations of IL-1ß and TNF-
alone, DC matured in the additional presence of PGE2 show
impaired IL-12 production and bias naive Th cell development toward the
Th2. The ability of DC to produce IL-12 is also suppressed by IL-10,
which in contrast to PGE2, inhibits their maturation. The
differences in the ability to produce IL-12, established during the
final DC maturation, are stable after the removal of modulatory
factors. Importantly, fully mature DC become unsusceptible to
PGE2 and IL-10. This indicates that the levels of IL-12
production in vivo, in mature DC interacting with Th cells within the
lymph nodes, are mainly predetermined at the stage of immature DC in
peripheral tissues. These data imply that the character of
pathogen-induced local inflammatory reaction can "instruct" local
DC to initiate Th1 or Th2-biased responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(5, 6). The cytokine-induced final maturation of DC is accompanied by a functional shift. While immature DC are able to take up Ag, the initiation of their maturation is accompanied by a transient enhancement of Ag uptake and a subsequent loss of this capacity. In parallel, the ability of maturing DC to stimulate naive Th cells and to initiate primary immune responses rapidly increases (1, 2). The ability of inflammatory signals to induce the final maturation of tissue-residing DC led to a "danger" concept (8), in which the initiation of Ag-specific immune responses is linked to the tissue damage via the resulting nonspecific inflammation. To what extent this early inflammatory reaction determines the character of the immune response initiated in naive Th cell population is less clear.
Already primary immune responses may show polarization toward the production of Th1- or Th2-type cytokines, depending on the route of entry and the type of pathogen (9, 10). A crucial factor in the generation of Th1-type responses is IL-12 (11). Mature DC can secrete IL-12 upon contact with CD40L-expressing T cells (12, 13) and, therefore, are implicated in the development of Th1-biased responses. IL-12 production in APC is strictly regulated (11). It was recently shown that IL-12 production in immature human DC is susceptible to the inhibition by IL-10, which at the same time inhibits the stimulatory potential of DC (14). Previously, we have shown that the presence of PGE2 during the early stages of DC development leads to the generation of IL-12-deficient cells, similar to immature CD1a+ DC in respect to morphology, expression of costimulatory molecules, and stimulatory capacity (15), but which display a CD1a-CD14+ phenotype. Those data indicated that the ability of developing APC to initiate Th1-type vs Th2-type responses may depend on the microenvironmental conditions of their development.
In the current study, we have addressed the question to what extent the
inflammatory mediators PGE2 and IL-10 modulate the final
maturation of CD1a+ DC with respect to phenotype and the
ability to pick up Ag, to stimulate naive Th cells, and to polarize Th
cell development into preferential production of Th1- or Th2-type
cytokines. We show that PGE2, in contrast to IL-10,
synergizes with IL-1ß and TNF- in the induction of phenotypical
and functional final maturation of DC. However, the
PGE2-promoted maturation results in
CD1a+CD83+ DC, which produce only low amounts
of IL-12 and bias the development of naive Th cells toward the
production of Th2-type cytokines. Since fully mature DC become
resistant to further modulation, these data imply that the ability of
DC to induce a particular type of Th response is predetermined in
peripheral tissues by the character of the local inflammatory response
that induces the final DC maturation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The following mAb were used: CD1a (OKT6; Ortho, Beerse,
Belgium), HLA-DR (L243; Becton Dickinson, Mountain View, CA), CD83
(HB15; Immunotech, Marseille, France), CD115 (GR12; Oncogene,
Cambridge, MA), CD80 (B7-24) and CD86 (1G10; both provided by
Innogenetics, Ghent, Belgium), CD40 (EA-5; a gift from Dr. T. LeBien,
University of Minnesota, Minneapolis, MN), mannose receptor (16) (15-2;
a gift from Dr. F. Noorman, Leiden, The Netherlands), CD45RA (2H4;
Coulter, Hialeah, FL), and CD45RO (UCHL-1; a gift from Dr. P. Beverly,
London, U.K.). IL-1ß ELISA (detection limit, 3 pg/ml) was performed
with use of a pair of anti-IL-1ß mAb, M421B and biotinylated
M420B, both obtained from Endogen (Cambridge, MA). TNF- ELISA
(detection limit, 20 pg/ml) was performed with a pair of
anti-TNF- mAb 58.175.08 and biotinylated 58.175.03, both
obtained from Biosource (Camarillo, CA).
Isolation of monocytes and naive Th cells
Monocytes were isolated from peripheral blood, as previously described (15). Naive CD45RA+CD4+ Th cells were isolated with use of the CD4-specific Dynabeads/Detatchabead system (Dynal, Oslo, Norway), followed by removal of CD45R0+ and residual HLA-DR+ cells by panning. This procedure yielded a population of >98% CD45RA+CD4+ Th cells.
Generation of immature CD1a+CD83- DC and induction of their final maturation
A procedure described by Sallusto (5) was used. Monocytes were
cultured in Iscove’s modified Dulbecco’s medium with 10% FCS
(HyClone, Logan, UT) in the presence of recombinant human
granulocyte-macrophage CSF (500 U/ml; a gift from Schering-Plough,
Uden, The Netherlands) and recombinant human (rh) IL-4 (250 U/ml; PBH,
Hannover, Germany). On day 6, the cultures consisted of uniformly
HLA-DR+, CD83-, CD115+ immature
DC, without any detectable CD3+ cells. Over 90% of the
cells expressed high levels of CD1a. For the following 48 h the
following factors were added: rhIL-1ß (sp. act., 5 x
107 U/ml; Boehringer Mannheim, Mannheim, Germany) and
rhuTNF- (sp. act., 108 U/ml; PBH) or LPS (Difco,
Detroit, MI), with or without PGE2 (Sigma, St. Louis, MO),
forskolin (Sigma), and rhIL-10 (PharMingen, San Diego, CA), as
indicated. All subsequent tests were performed after removal of
IL-1ß, TNF-, PGE2, IL-10, granulocyte-macrophage CSF,
and IL-4.
Analysis of IL-12 production
On day 8 DC were harvested and washed extensively. Either the
cells (4 x 104 cells in 200 µl) were stimulated on
the same day, or DC were first cultured for an additional 24 h in
the absence of modulatory agents, then washed and stimulated
subsequently. DC were stimulated for 24 h with soluble rCD40L (17)
(1 µg/ml; a gift from Immunex, Seattle, WA) in combination with
rhIFN-
(1000 U/ml; a gift from Dr. P. H. van der Meide,
Biomedical Primate Research Centre, Rijswijk, The Netherlands)
or were cocultured with CD4+ T cells in the presence of
superantigen (SEB; 1 ng/ml; Serva, Heidelberg, Germany). IL-12 p70
contents in the 24-h supernatants were measured with specific ELISA
(sensitivity, 2 pg/ml) (18).
Induction of memory-type cytokines in maturing Th cells
Naive Th cells (2 x 104) were activated by
irradiated (3000 rad) autologous DC (2 x 104) in the
presence of SEB (1 ng/ml). When indicated, rhIL-12 (200 U/ml; a gift
from Dr. M. Gately, Hoffmann-La Roche, Nutley, NJ) was added at the
beginning of the cultures. On day 5, rhIL-2 (10 U/ml; a gift from Cetus
Corp., Emeryville, CA) was added, and the cultures were expanded for
next 9 days. On day 14 the quiescent Th cells were restimulated with
CD3 mAb (CLB-T3/3; CLB) plus CD28 mAb (CLB-CD28/1; CLB), as previously
described (19). The levels of IFN-, IL-4, and IL-5 in 24-h
supernatants were analyzed by specific ELISA, as previously described
(15).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in the
induction of mature DC phenotype and functions
Day 6 monocyte-derived DC (5) expressed M-CSF receptor (CD115) but
lacked CD83 expression. Exposure of such immature DC to high
concentrations of IL-1ß (10 ng/ml) and TNF- (25 ng/ml), the
cytokines known to induce final DC maturation (3, 4, 6), resulted in a
rapid disappearance of CD115 and the acquisition of the mature DC
marker CD83 (Fig. 1
A). One
hundred-fold lower concentrations of IL-1ß (0.1 ng/ml) and TNF-
(0.25 ng/ml) were virtually noneffective, inducing the above-described
changes in only a small percentage of DC. In the presence of IL-10 (50
U/ml), even the high IL-1ß and TNF- concentrations induced CD83
expression in only 30 to 50% of DC, confirming the previously
postulated role of IL-10 as a factor preventing DC activation (20, 21, 22).
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, rendering them effective at 100-fold lower concentrations
(Fig. 1
A). This effect of PGE2 was evident at
10-8 M and was optimal at 10-7 M. These
effects of PGE2 are mediated by the elevation of
intracellular cAMP levels, since forskolin (10-5 M), an
activator of adenylate cyclase, also facilitated DC maturation at low
concentrations of IL-1ß and TNF-.
Interestingly, however, in the absence of inflammatory cytokines,
PGE2 was completely ineffective, even at the concentration
of 10-6 M, implying that PGE2 is only a
cofactor for IL-1ß- and TNF--induced DC maturation. Similarly,
forskolin was completely ineffective unless small amounts of the
inflammatory cytokines were added (Fig. 1A). Therefore,
PGE2 appears to act differently from IL-1ß, TNF-, and
LPS, which can all induce final DC maturation also when used alone (3, 6). This maturation-promoting effect of PGE2 was not
associated with any detectable elevation of IL-1ß or TNF- levels
in the DC cultures exposed to low concentrations of these factors (Fig. 1B).
Facilitation of DC maturation by PGE2 was reflected by the
up-regulation of costimulatory molecules CD80 and CD86 and by the
down-regulation of the mannose receptor, resulting in the phenotype
similar to DC maturing in the high concentrations of IL-1ß and
TNF- (Fig. 1C). The same results were obtained with
forskolin (not shown).
At the functional level, PGE2 promoted the shift from
Ag-trapping into immunostimulatory cells. PGE2 synergized
with IL-1ß and TNF- in the reduction of the ability of maturing DC
to take up mannosylated BSA (Fig. 1C) and in the
up-regulation of their ability to stimulate naive Th cells (Fig. 2). In contrast to PGE2,
IL-10 preserved the ability of IL-1ß- and TNF--exposed DC to take
up mannosylated BSA (data not shown) and inhibited the increase in
their stimulatory capacity for naive Th cells (Fig. 2). This inhibitory
effect was especially clear when low amounts of DC were added to naive
Th cell cultures, consistent with the observation that a proportion of
DC escaped the suppressive effect of IL-10 (Fig. 1A).
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Although phenotypically identical with the cells matured in the
presence of high concentrations of IL-1ß and TNF- alone, DC
matured in the additional presence of PGE2 showed a reduced
capacity to produce IL-12. This was seen both after a powerful
stimulation with soluble CD40L in the presence of IFN-, a mode of
stimulation corresponding to the interaction between Th cells and APC
(25, 26), as well as when DC were cocultured with CD4+ Th
cells in the presence of SEB (Fig. 3A), in which case the levels
of IL-12 induced were approximately sevenfold lower (see Fig. 3
legend), but showed the same pattern of inhibition. The presence of
IL-10 had a similar IL-12 inhibitory effect. These observations were
reproduced in 12 donors. The PGE2 effect was seen at doses
as low as 10-9 M and was optimal at 10-7 M
(Fig. 3B), indicating that PGE2 is effective at
physiologic concentrations, such as those found at inflammatory sites
or in tumors (23, 24).
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B), suggesting that PGE2 and
IL-10, whenever present in the lymph nodes, will have little effect.
The decreased IL-12 production was still present in the DC that were
induced to mature in the presence of PGE2 or IL-10, but
were further cultured for an additional 24 h in the absence of
these factors before stimulation (Fig. 3C). These findings
indicate that PGE2 and IL-10 stably impair IL-12 production
in maturing DC, and they suggest that the ability of DC to produce
IL-12 after migration to the draining lymph nodes will reflect a fixed
level, resulting from the composition of inflammatory environment at
the site of their activation.
PGE2-promoted DC maturation results in their Th2 cell-biasing function
We have reported previously that priming of naive Th cells by
totally IL-12-deficient APC leads to the generation of type 2
cytokine-biased responses (15). Therefore, we tested whether the
presence of PGE2 during the final DC maturation, although
resulting in only a partial inhibition of IL-12, also affects naive Th
cell priming. Purified naive CD4+CD45RA+ T
cells were stimulated with SEB presented by the two populations of
fully mature DC, obtained in the absence (control DC) or the presence
of PGE2. Naive Th cells primed with control DC or
PGE2-preexposed DC expanded to a similar extent
(
2000-fold). These in vitro matured T cells were restimulated on day
14 to determine the production of memory-type Th cytokines.
As shown in Figure 4A, the
priming of Th cells by the PGE2-preexposed DC resulted in
the enhanced ability of maturing Th cells to produce Th2-type
cytokines, IL-4 (approximately twofold) and IL-5 (approximately
fourfold), and their diminished ability to produce IFN-
(approximately twofold), compared with cells primed by control DC. This
Th2-driving capacity was overruled by exogenous IL-12 (Fig. 4B). The addition of IL-12 also modified the development of
Th cells primed by control DC, resulting in the generation of Th1-like,
instead of Th0-like, cells from naive precursors. This is in accord
with the previous reports, showing that, in the absence of external
stimuli, unmodified DC induce Th0-like cytokine profiles in vitro (27)
and in vivo (28). This results from the fact that naive Th cells induce
only limited amounts of IL-12 during their interaction with DC (27).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The two IL-12-inhibiting factors tested in this study, PGE2
and IL-10, showed a strikingly different impact on the final maturation
of DC. While IL-10 was confirmed to act as an inhibitory factor,
PGE2 was demonstrated to act as a cofactor in IL-1ß- and
TNF--induced DC maturation, lowering the requirement for these
inflammatory cytokines by a 100-fold. Due to its different molecular
character as a prostanoid, but also due to a different mode of action
compared with inflammatory cytokines or LPS, PGE2 appears
to be a different type of DC maturation-promoting factor. In contrast
to IL-1ß, TNF-, or LPS, which in high concentrations can induce
the DC maturation by themselves, the effect of PGE2, even
at the high concentration of 10-6 M, was totally dependent
on the presence of low amounts of the inflammatory cytokines. When
forskolin was used to document the cAMP dependence of PGE2
action, its activity also required the presence of low concentrations
of IL-1ß and TNF-. Only in those experiments in which a
spontaneous maturation was already observed in a part of the DC on day
6, probably due to the activation of cells during the initial culture
period, the addition of PGE2 alone led to maturation of the
remaining cells (data not shown). This finding suggests that either
small amounts of endogenously produced inflammatory cytokines could
synergize with PGE2 or that at a certain later stage of
final DC maturation PGE2 becomes capable of completing this
process by itself. This maturation-promoting activity of
PGE2 was not accompanied by any elevation of IL-1ß or
TNF- levels in the cultures of maturing DC exposed to low doses of
these inflammatory cytokines (Fig. 1B), arguing against an
indirect action of PGE2, mediated by the induction of
endogenous production of these cytokines. Despite the view that
PGE2 is a suppressive inflammatory factor, these data
indicate that PGE2 contributes to the initiation of primary
immune responses by facilitating the cytokine-induced final maturation
and the increase in immunostimulatory capacity of DC.
The current results confirm the role of PGE2 as a
Th2-promoting factor, acting at the APC level (15). They show that the
maturation of DC in the PGE2-rich environment results in
cells that produce reduced amounts of bioactive IL-12 p70 heterodimer
after subsequent contact with Th cells. Although it was recently
reported that the exposure of immature DC to PGE2 results
in the induction of the inactive p40 subunit of IL-12 (29), in our
hands such p40 induction by PGE2 alone or in combination
with TNF- is not accompanied by the production of bioactive p70
heterodimer of IL-12 (P. Kalinski, J. H. N. Schuitemaker, and M.
L. Kapsenberg, manuscript in preparation). This is in contrast
to LPS stimulation, which results in the production of both p40 as well
as the biologically relevant p70 heterodimer. These observations
confirm that the production of p40 and that of p70 are regulated
separately, which was previously demonstrated in monocytes
(18).
Although the DC matured in high concentrations of IL-1ß and TNF-
alone or in the additional presence of PGE2 show the
similar expression of maturation markers and costimulatory molecules,
the PGE2-matured DC bias the differentiation of naive Th
cells toward Th2. This Th2 bias was overruled by the addition of
exogenous IL-12. In the presence of IL-12, the priming by both DC types
resulted in the generation of Th1-like cells. This finding argues
against an involvement of any specific Th2-driving factor(s) produced
by PGE2-modified DC, and instead suggests the crucial role
of IL-12 differences in the differential priming of naive Th cells.
The strong differences in the ability to produce IL-12 between phenotypically identical DC observed in this study indicate that CD1a+ DC per se should not be considered a Th1-steering APC type. This is in line with a previous study of Ronchese et al. (28), which showed that DC are effective inducers of both Th1-type as well as Th2-type cytokines in vivo. Instead, our data suggest that a single APC type, i.e., the DC, may have differential ability to induce Th1-type or Th2-type Th cells depending on the tissue of origin and the conditions of their maturation. This also implies that the manner of inducing the maturation of DC used for immunotherapy may be crucial to the success of treatment, due to the different cytokine patterns of the responses induced by phenotypically similar DC.
The deficiency in IL-12 production induced by PGE2 and IL-10 was preserved for at least 24 h after removing the modulatory factors, suggesting that in vivo, when induced in the peripheral tissues, the IL-12 deficit will be present in the cells reaching the lymph nodes. A striking finding was that IL-12 production in fully mature DC was resistant to subsequent modulation. The susceptibility of DC to functional polarization by PGE2 and IL-10 during their final maturation and the subsequent loss of such susceptibility in fully mature cells resemble a narrow time window in which activated immature DC can efficiently take up Ag and a loss of Ag uptake capacity in mature DC (6). Both these phenomena may help to selectively sample the environment, restricting the acquisition of both antigenic peptides and modulatory signals to the relevant site of pathogen entry. This may reduce the risk of picking up irrelevant signals on the way to the lymph nodes and, in the second case, may allow for an independent regulation of cytokine profiles in T cells responding to different Ags within a single lymph node.
The current observations are consistent with a concept of a DC as a go-between, constituting the link between the local natural defense mechanisms and the measures of specific immunity. It is generally accepted that DC, activated by a nonspecific tissue response to the pathogen, instruct the immune system to initiate an Ag-specific response by providing the naive Th cells with signal 1 (Ag) and signal 2 (costimulation). The current data imply that this nonspecific tissue response, depending on its character, may also be able to instruct the locally activated DC to provide naive Th cells with a signal 3 (polarization), determining the type of response to be initiated.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Pawe Kaliski, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. E-mail address:
3 Abbreviations used in this paper: DC, dendritic cells; CD40L, CD40 ligand; rh, recombinant human; SEB, staphylococcal enterotoxin B.
Received for publication December 1, 1997. Accepted for publication May 19, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 M. Galgani, V. De Rosa, S. De Simone, A. Leonardi, U. D'Oro, G. Napolitani, A. M. Masci, S. Zappacosta, and L. Racioppi Cyclic AMP Modulates the Functional Plasticity of Immature Dendritic Cells by Inhibiting Src-like Kinases through Protein Kinase A-mediated Signaling J. Biol. Chem., July 30, 2004; 279(31): 32507 - 32514. [Abstract] [Full Text] [PDF]
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S. Kubo, H. K. Takahashi, M. Takei, H. Iwagaki, T. Yoshino, N. Tanaka, S. Mori, and M. Nishibori E-Prostanoid (EP)2/EP4 Receptor-Dependent Maturation of Human Monocyte-Derived Dendritic Cells and Induction of Helper T2 Polarization J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1213 - 1220. [Abstract] [Full Text] [PDF]
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A. Mazzoni and D. M. Segal Controlling the Toll road to dendritic cell polarization J. Leukoc. Biol., May 1, 2004; 75(5): 721 - 730. [Abstract] [Full Text] [PDF]
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R. Rouas, P. Lewalle, F. El Ouriaghli, B. Nowak, H. Duvillier, and P. Martiat Poly(I:C) used for human dendritic cell maturation preserves their ability to secondarily secrete bioactive IL-12 Int. Immunol., May 1, 2004; 16(5): 767 - 773. [Abstract] [Full Text] [PDF]
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C. C. Bowman and K. L. Bost Cyclooxygenase-2-Mediated Prostaglandin E2 Production in Mesenteric Lymph Nodes and in Cultured Macrophages and Dendritic Cells after Infection with Salmonella J. Immunol., February 15, 2004; 172(4): 2469 - 2475. [Abstract] [Full Text] [PDF]
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 G. Pynaert, P. Rottiers, A. Haegeman, S. Sehra, T. Van Belle, J. Korf, and J. Grooten Antigen Presentation by Local Macrophages Promotes Nonallergic Airway Responses in Sensitized Mice Am. J. Respir. Cell Mol. Biol., November 1, 2003; 29(5): 634 - 641. [Abstract] [Full Text]
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S. Miyazaki, H. Tsuda, M. Sakai, S. Hori, Y. Sasaki, T. Futatani, T. Miyawaki, and S. Saito Predominance of Th2-promoting dendritic cells in early human pregnancy decidua J. Leukoc. Biol., October 1, 2003; 74(4): 514 - 522. [Abstract] [Full Text] [PDF]
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M. Mohty, A. Vialle-Castellano, J. A. Nunes, D. Isnardon, D. Olive, and B. Gaugler IFN-{alpha} Skews Monocyte Differentiation into Toll-Like Receptor 7-Expressing Dendritic Cells with Potent Functional Activities J. Immunol., October 1, 2003; 171(7): 3385 - 3393. [Abstract] [Full Text] [PDF]
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A. Soruri, J. Riggert, T. Schlott, Z. Kiafard, C. Dettmer, and J. Zwirner Anaphylatoxin C5a Induces Monocyte Recruitment and Differentiation into Dendritic Cells by TNF-{alpha} and Prostaglandin E2-Dependent Mechanisms J. Immunol., September 1, 2003; 171(5): 2631 - 2636. [Abstract] [Full Text] [PDF]
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H. C. Heystek, A.-C. Thierry, P. Soulard, and C. Moulon Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1-polarizing capacity Int. Immunol., July 1, 2003; 15(7): 827 - 835. [Abstract] [Full Text] [PDF]
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H. Harizi, C. Grosset, and N. Gualde Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes J. Leukoc. Biol., June 1, 2003; 73(6): 756 - 763. [Abstract] [Full Text] [PDF]
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A. S. Yang and E. C. Lattime Tumor-induced Interleukin 10 Suppresses the Ability of Splenic Dendritic Cells to Stimulate CD4 and CD8 T-Cell Responses Cancer Res., May 1, 2003; 63(9): 2150 - 2157. [Abstract] [Full Text] [PDF]
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P. L. Vieira, H. C. Heystek, J. Wormmeester, E. A. Wierenga, and M. L. Kapsenberg Glatiramer Acetate (Copolymer-1, Copaxone) Promotes Th2 Cell Development and Increased IL-10 Production Through Modulation of Dendritic Cells J. Immunol., May 1, 2003; 170(9): 4483 - 4488. [Abstract] [Full Text] [PDF]
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M. Dauer, B. Obermaier, J. Herten, C. Haerle, K. Pohl, S. Rothenfusser, M. Schnurr, S. Endres, and A. Eigler Mature Dendritic Cells Derived from Human Monocytes Within 48 Hours: A Novel Strategy for Dendritic Cell Differentiation from Blood Precursors J. Immunol., April 15, 2003; 170(8): 4069 - 4076. [Abstract] [Full Text] [PDF]
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A. M. Woltman and C. van Kooten Functional modulation of dendritic cells to suppress adaptive immune responses J. Leukoc. Biol., April 1, 2003; 73(4): 428 - 441. [Abstract] [Full Text] [PDF]
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M. Vulcano, S. Struyf, P. Scapini, M. Cassatella, S. Bernasconi, R. Bonecchi, A. Calleri, G. Penna, L. Adorini, W. Luini, et al. Unique Regulation of CCL18 Production by Maturing Dendritic Cells J. Immunol., April 1, 2003; 170(7): 3843 - 3849. [Abstract] [Full Text] [PDF]
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 S. Sharma, M. Stolina, S.-C. Yang, F. Baratelli, J. F. Lin, K. Atianzar, J. Luo, L. Zhu, Y. Lin, M. Huang, et al. Tumor Cyclooxygenase 2-dependent Suppression of Dendritic Cell Function Clin. Cancer Res., March 1, 2003; 9(3): 961 - 968. [Abstract] [Full Text] [PDF]
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A. Boonstra, C. Asselin-Paturel, M. Gilliet, C. Crain, G. Trinchieri, Y.-J. Liu, and A. O'Garra Flexibility of Mouse Classical and Plasmacytoid-derived Dendritic Cells in Directing T Helper Type 1 and 2 Cell Development: Dependency on Antigen Dose and Differential Toll-like Receptor Ligation J. Exp. Med., January 6, 2003; 197(1): 101 - 109. [Abstract] [Full Text] [PDF]
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S. Al-Darmaki, H. A. Schenkein, J. G. Tew, and S. E. Barbour Differential Expression of Platelet-Activating Factor Acetylhydrolase in Macrophages and Monocyte-Derived Dendritic Cells J. Immunol., January 1, 2003; 170(1): 167 - 173. [Abstract] [Full Text] [PDF]
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N. Omata, M. Yasutomi, A. Yamada, H. Iwasaki, M. Mayumi, and Y. Ohshima Monocyte Chemoattractant Protein-1 Selectively Inhibits the Acquisition of CD40 Ligand-Dependent IL-12-Producing Capacity of Monocyte-Derived Dendritic Cells and Modulates Th1 Immune Response J. Immunol., November 1, 2002; 169(9): 4861 - 4866. [Abstract] [Full Text] [PDF]
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A. E. Lokshin, P. Kalinski, R. R. Sassi, R. B. Mailliard, J. Muller-Berghaus, W. J. Storkus, X. Peng, A. M. Marrangoni, R. P. Edwards, and E. Gorelik Differential regulation of maturation and apoptosis of human monocyte-derived dendritic cells mediated by MHC class II Int. Immunol., September 1, 2002; 14(9): 1027 - 1037. [Abstract] [Full Text] [PDF]
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E. Scandella, Y. Men, S. Gillessen, R. Forster, and M. Groettrup Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells Blood, July 30, 2002; 100(4): 1354 - 1361. [Abstract] [Full Text] [PDF]
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T. Luft, M. Jefford, P. Luetjens, T. Toy, H. Hochrein, K.-A. Masterman, C. Maliszewski, K. Shortman, J. Cebon, and E. Maraskovsky Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E2 regulates the migratory capacity of specific DC subsets Blood, July 30, 2002; 100(4): 1362 - 1372. [Abstract] [Full Text] [PDF]
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R. W. Sanders, E. C. de Jong, C. E. Baldwin, J. H. N. Schuitemaker, M. L. Kapsenberg, and B. Berkhout Differential Transmission of Human Immunodeficiency Virus Type 1 by Distinct Subsets of Effector Dendritic Cells J. Virol., June 27, 2002; 76(15): 7812 - 7821. [Abstract] [Full Text] [PDF]
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 S. Wei, F. Marches, J. Borvak, W. Zou, J. Channon, M. White, J. Radke, M.-F. Cesbron-Delauw, and T. J. Curiel Toxoplasma gondii-Infected Human Myeloid Dendritic Cells Induce T-Lymphocyte Dysfunction and Contact-Dependent Apoptosis Infect. Immun., April 1, 2002; 70(4): 1750 - 1760. [Abstract] [Full Text] [PDF]
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H. Harizi, M. Juzan, V. Pitard, J.-F. Moreau, and N. Gualde Cyclooxygenase-2-Issued Prostaglandin E2 Enhances the Production of Endogenous IL-10, Which Down-Regulates Dendritic Cell Functions J. Immunol., March 1, 2002; 168(5): 2255 - 2263. [Abstract] [Full Text] [PDF]
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E. C. de Jong, P. L. Vieira, P. Kalinski, J. H. N. Schuitemaker, Y. Tanaka, E. A. Wierenga, M. Yazdanbakhsh, and M. L. Kapsenberg Microbial Compounds Selectively Induce Th1 Cell-Promoting or Th2 Cell-Promoting Dendritic Cells In Vitro with Diverse Th Cell-Polarizing Signals J. Immunol., February 15, 2002; 168(4): 1704 - 1709. [Abstract] [Full Text] [PDF]
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H. H. Smits, E. C. de Jong, J. H. N. Schuitemaker, T. B. H. Geijtenbeek, Y. van Kooyk, M. L. Kapsenberg, and E. A. Wierenga Intercellular Adhesion Molecule-1/LFA-1 Ligation Favors Human Th1 Development J. Immunol., February 15, 2002; 168(4): 1710 - 1716. [Abstract] [Full Text] [PDF]
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H. Miyaura and M. Iwata Direct and Indirect Inhibition of Th1 Development by Progesterone and Glucocorticoids J. Immunol., February 1, 2002; 168(3): 1087 - 1094. [Abstract] [Full Text] [PDF]
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G. M. del Hoyo, P. Martin, C. F. Arias, A. R. Marin, and C. Ardavin CD8alpha + dendritic cells originate from the CD8alpha - dendritic cell subset by a maturation process involving CD8alpha , DEC-205, and CD24 up-regulation Blood, February 1, 2002; 99(3): 999 - 1004. [Abstract] [Full Text] [PDF]
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 M. F. Lipscomb and B. J. Masten Dendritic Cells: Immune Regulators in Health and Disease Physiol Rev, January 1, 2002; 82(1): 97 - 130. [Abstract] [Full Text] [PDF]
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R. Jotwani, A. K. Palucka, M. Al-Quotub, M. Nouri-Shirazi, J. Kim, D. Bell, J. Banchereau, and C. W. Cutler Mature Dendritic Cells Infiltrate the T Cell-Rich Region of Oral Mucosa in Chronic Periodontitis: In Situ, In Vivo, and In Vitro Studies J. Immunol., October 15, 2001; 167(8): 4693 - 4700. [Abstract] [Full Text] [PDF]
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G. Caron, Y. Delneste, E. Roelandts, C. Duez, J.-Y. Bonnefoy, J. Pestel, and P. Jeannin Histamine Polarizes Human Dendritic Cells into Th2 Cell-Promoting Effector Dendritic Cells J. Immunol., October 1, 2001; 167(7): 3682 - 3686. [Abstract] [Full Text] [PDF]
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 E. PANTHER, M. IDZKO, Y. HEROUY, H. RHEINEN, P. J. GEBICKE-HAERTER, U. MROWIETZ, S. DICHMANN, and J. NORGAUER Expression and function of adenosine receptors in human dendritic cells FASEB J, September 1, 2001; 15(11): 1963 - 1970. [Abstract] [Full Text] [PDF]
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P. Kalinski, P. L. Vieira, J. H. N. Schuitemaker, E. C. de Jong, and M. L. Kapsenberg Prostaglandin E2 is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer Blood, June 1, 2001; 97(11): 3466 - 3469. [Abstract] [Full Text] [PDF]
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O. Alpan, G. Rudomen, and P. Matzinger The Role of Dendritic Cells, B Cells, and M Cells in Gut-Oriented Immune Responses J. Immunol., April 15, 2001; 166(8): 4843 - 4852. [Abstract] [Full Text] [PDF]
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S. Corinti, C. Albanesi, A. la Sala, S. Pastore, and G. Girolomoni Regulatory Activity of Autocrine IL-10 on Dendritic Cell Functions J. Immunol., April 1, 2001; 166(7): 4312 - 4318. [Abstract] [Full Text] [PDF]
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T. Ito, R. Amakawa, M. Inaba, S. Ikehara, K. Inaba, and S. Fukuhara Differential Regulation of Human Blood Dendritic Cell Subsets by IFNs J. Immunol., March 1, 2001; 166(5): 2961 - 2969. [Abstract] [Full Text] [PDF]
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A. la Sala, D. Ferrari, S. Corinti, A. Cavani, F. Di Virgilio, and G. Girolomoni Extracellular ATP Induces a Distorted Maturation of Dendritic Cells and Inhibits Their Capacity to Initiate Th1 Responses J. Immunol., February 1, 2001; 166(3): 1611 - 1617. [Abstract] [Full Text] [PDF]
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J. Banchereau, B. Pulendran, R. Steinman, and K. Palucka Will the Making of Plasmacytoid Dendritic Cells in Vitro Help Unravel Their Mysteries? J. Exp. Med., December 18, 2000; 192(12): f39 - f44. [Full Text] [PDF]
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L. M. Lopes, A. Maroof, G. Dougan, and B. M. Chain Inhibition of T-cell Response by Escherichia coli Heat-Labile Enterotoxin-Treated Epithelial Cells Infect. Immun., December 1, 2000; 68(12): 6891 - 6895. [Abstract] [Full Text] [PDF]
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 S. E. Ullrich and H. J. Lyons Mechanisms Involved in the Immunotoxicity Induced by Dermal Application of JP-8 Jet Fuel Toxicol. Sci., December 1, 2000; 58(2): 290 - 298. [Abstract] [Full Text] [PDF]
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W. Zou, J. Borvak, F. Marches, S. Wei, P. Galanaud, D. Emilie, and T. J. Curiel Macrophage-Derived Dendritic Cells Have Strong Th1-Polarizing Potential Mediated by {beta}-Chemokines Rather Than IL-12 J. Immunol., October 15, 2000; 165(8): 4388 - 4396. [Abstract] [Full Text] [PDF]
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C.-C. J. Chang, A. Wright, and J. Punnonen Monocyte-Derived CD1a+ and CD1a- Dendritic Cell Subsets Differ in Their Cytokine Production Profiles, Susceptibilities to Transfection, and Capacities to Direct Th Cell Differentiation J. Immunol., October 1, 2000; 165(7): 3584 - 3591. [Abstract] [Full Text] [PDF]
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D. A. Schmitt and S. E. Ullrich Exposure to Ultraviolet Radiation Causes Dendritic Cells/Macrophages to Secrete Immune-Suppressive IL-12p40 Homodimers J. Immunol., September 15, 2000; 165(6): 3162 - 3167. [Abstract] [Full Text] [PDF]
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 M. L. KAPSENBERG, C. M. U. HILKENS, T. C. M. T. van der POUW KRAAN, E. A. WIERENGA, and P. KALINSKI Atopic Allergy: A Failure of Antigen-Presenting Cells to Properly Polarize Helper T Cells? Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S76 - 80. [Full Text] [PDF]
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H. Kahlert, E. Grage-Griebenow, H.-T. Stuwe, O. Cromwell, and H. Fiebig T Cell Reactivity with Allergoids: Influence of the Type of APC J. Immunol., August 15, 2000; 165(4): 1807 - 1815. [Abstract] [Full Text] [PDF]
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C. C. Termeer, J. Hennies, U. Voith, T. Ahrens, J. M. Weiss, P. Prehm, and J. C. Simon Oligosaccharides of Hyaluronan Are Potent Activators of Dendritic Cells J. Immunol., August 15, 2000; 165(4): 1863 - 1870. [Abstract] [Full Text] [PDF]
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C. S. Subauste and M. Wessendarp Human Dendritic Cells Discriminate Between Viable and Killed Toxoplasma gondii Tachyzoites: Dendritic Cell Activation After Infection with Viable Parasites Results in CD28 and CD40 Ligand Signaling That Controls IL-12-Dependent and -Independent T Cell Production of IFN-{gamma} J. Immunol., August 1, 2000; 165(3): 1498 - 1505. [Abstract] [Full Text] [PDF]
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Y. Tada, A. Asahina, K. Nakamura, M. Tomura, H. Fujiwara, and K. Tamaki Granulocyte/Macrophage Colony-Stimulating Factor Inhibits IL-12 production of Mouse Langerhans Cells J. Immunol., May 15, 2000; 164(10): 5113 - 5119. [Abstract] [Full Text] [PDF]
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P. L. Vieira, E. C. de Jong, E. A. Wierenga, M. L. Kapsenberg, and P. Kalinski Development of Th1-Inducing Capacity in Myeloid Dendritic Cells Requires Environmental Instruction J. Immunol., May 1, 2000; 164(9): 4507 - 4512. [Abstract] [Full Text] [PDF]
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P. Kalinski, J. H. N. Schuitemaker, C. M. U. Hilkens, E. A. Wierenga, and M. L. Kapsenberg Final Maturation of Dendritic Cells Is Associated with Impaired Responsiveness to IFN-{gamma} and to Bacterial IL-12 Inducers: Decreased Ability of Mature Dendritic Cells to Produce IL-12 During the Interaction with Th Cells J. Immunol., March 15, 1999; 162(6): 3231 - 3236. [Abstract] [Full Text] [PDF]
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I-C. Ho, J. P. Arm, C. O. Bingham III, A. Choi, K. F. Austen, and L. H. Glimcher A Novel Group of Phospholipase A2s Preferentially Expressed in Type 2 Helper T Cells J. Biol. Chem., May 18, 2001; 276(21): 18321 - 18326. [Abstract] [Full Text] [PDF]
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