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Committee on Immunology, Department of Pathology, Division of Biological Sciences, University of Chicago, Chicago, IL 60637
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-secreting
Th cells, as a result of its ability to inhibit DC IL-12 secretion. The
goal of the present study was to identify how IFN-ß negatively
regulates IL-12 secretion by DC. We report that in our Th cell
differentiation model, DC IL-12 secretion is dependent on the
CD40L/CD40 accessory pathway, and, utilizing a Th cell-free system, we
find that IFN-ß inhibits anti-CD40 mAb-induced DC secretion of
the p40 chain of the IL-12 heterodimer. In addition, we show that
IFN-ß-mediated inhibition of CD40 signaling does not interfere with
all signaling pathways emanating from CD40, since anti-CD40
mAb-induced DC IL-6 secretion is augmented by IFN-ß. Thus, our
results demonstrate that signaling from CD40 is differentially
regulated by IFN-ß. A second critical element of innate immunity
involves the response against components of bacterial membranes such as
LPS. DC respond to LPS by secreting IL-6 and IL-12. In contrast to
CD40-dependent IL-6 and IL-12 secretion, we find that LPS-induced DC
secretion of p40 IL-12 and IL-6 is not affected by IFN-ß. Our
findings show that IFN-ß influences the generation of acquired immune
responses through its regulation of CD40-dependent DC
functions. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Type I IFNs, IFN-
and -ß, are produced by many cell types (e.g.,
macrophages, T cells, keratinocytes, and Langerhans cells) in response
to viral infection. Type I IFNs have a broad range of immunomodulatory
effects, including inhibition of viral replication and stimulation of
NK cell activation (2, 3). We have recently shown that
type I IFNs can also influence Th cell differentiation by inhibiting
IL-12 secretion by mature monocyte-derived DC (4). IL-12
is a cytokine critical for both NK cell IFN- production and
the generation of IFN--secreting Th1 cells (5). The
cytokine is a heterodimeric protein consisting of a p35 and a p40
chain, and it is often induced in phagocytic cells by stimuli which
include bacteria, intracellular parasites, and some viruses
(6). T cell-dependent stimulation of DC and macrophages
through CD40 or MHC class II can also induce these cells to secrete
IL-12 (7). Regulation of IL-12 production during the early
stages of infection is a critical factor in determining the outcome of
a subsequent immune response. IL-12-induced IFN- secretion by T
cells and NK cells potentiates phagocytosis, production of NO, and
oxidative burst, resulting in enhanced destruction of pathogens
(5). In turn, IFN- positively regulates IL-12
production to further amplify the inflammatory response, thus
necessitating negative regulators of IL-12 to control inflammation and
prevent destruction of host tissues (6). Other cytokines
that are known to affect IL-12 production and function include IL-4,
IL-10, and TGF-ß (7, 8, 9).
We have previously described an in vitro human naive Th cell
differentiation model in which effector Th cells are generated from
naive Th cells stimulated with monocyte-derived mature DC and
immobilized anti-CD3 mAb (4). The Th cells that are
generated secrete only Th1 cell cytokines, including IFN-,
lymphotoxin-, and TNF- , whereas the Th2 cell cytokines IL-4,
IL-5, and IL-13 are not detected. In this model, type I IFNs were found
to inhibit DC-mediated costimulation required for the generation of
IFN--secreting Th cells (4). Our initial findings
indicated that IFN-ß mediated this effect through its inhibition of
IL-12 heterodimer (p70) secretion.
We now describe studies aimed at identifying the mechanism by which IFN-ß inhibits IL-12 secretion by DC. We report that IFN-ß differentially regulates CD40-induced cytokine production in human DC by a direct effect on the CD40L/CD40 accessory molecule pathway. Specifically, IFN-ß was found to inhibit T cell-dependent, CD40-induced DC production of the p40 chain of the IL-12 heterodimer and to synergize with signals through CD40 to enhance DC IL-6 secretion. Interestingly, IFN-ß had no effect on T cell-independent, LPS-induced DC secretion of p40 IL-12 and IL-6. These results indicate that IFN-ß can be an important immunoregulatory molecule during the initiation of acquired immunity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD14+ blood-derived monocytes were
isolated from peripheral blood by counterflow centrifugal elutriation
(10) and frozen at 4 x 107
cells/ml. Cells were thawed as needed and cultured in 6-well tissue
culture plates (Costar, Cambridge, MA) at 3.3 x
106/ml in complete culture media (RPMI 1640; Life
Technologies, Gaithersburg, MD) supplemented with 10% FBS, 20 mM
L-glutamine, 100 IU/ml penicillin, and 100 µg/ml
streptomycin (BioWhittaker, Walkersville, MD). IL-4 and GM-CSF
(PharMingen, San Diego, CA) were added to the culture at 30 ng/ml at
days 1, 4, and 7 of the culture. At day 5 of culture TNF-
(PharMingen) was added at 100 U/ml. Cells were harvested on day 9 with
Versene (BioWhittaker), washed twice with Ca/Mg-free PBS, and used
immediately for flow cytofluorometric analysis and T cell
differentiation assays.
Isolation of naive human CD4+CD45RA+ CD45RO- T cells
Human PBMC from buffy coats of healthy anonymous donors (HIV-1 negative, hepatitis negative) (Lifesource, Chicago, IL) were isolated by Ficoll gradient centrifugation. Resting CD4+CD45RA+CD45RO- T cells were obtained by negative selection with Abs and magnetic beads as described (11). CD45RA+ cells were 95% pure by flow cytofluorometric analysis using mouse mAb: CD45RA-PE (clone B-C15; BioSource International, Camarillo, CA) and CD45RO-FITC (clone UCHL1; Caltag, South San Francisco, CA). Staining of cells with Abs was conducted according to standard procedures as described previously (11) and evaluated using a FACScan (Becton Dickinson, San Jose, CA).
Stimulation conditions
Naive CD4+ T cells (5 x
105) were cultured in a volume of 2 ml of
complete culture media with irradiated allogenic DC (5 x
104) for 48 h in 24-well plates (Costar)
that had been coated overnight at 4°C with 0.5 ml of 1 µg/ml of
CD3 mAb OKT3 in PBS. At the beginning of each
(re)stimulation, recombinant human IFN-ß-1a (Biogen,
Cambridge, MA) was added at 5 ng/ml. In some experiments, DC (5 x
105) were stimulated for 48 h with 5 µg/ml
LPS (Sigma, St. Louis, MO). For blocking of the CD40L/CD40 accessory
pathway, a humanized anti-CD40L mAb (5C8) was generously provided
by Dr. Linda Burkly (Biogen). Human Ig control Ab was purchased from
Sigma. The data in Figs. 1
and 4 were derived from independent
experiments with two different T cell and two different DC donors in
four different T cell and DC donor combinations. In the sets of
experiments shown in Figs. 2, 3, 5, and 6, the T cells and DC from
different donors were used only once, for a single experiment.
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RII (CD32, 2.5 x 105; line
DT-70, generously provided by Dr. Lewis Lanier, DNAX, Palo Alto, CA).
MOPC21, mouse IgG1 (Organon Teknika, Durham, NC) was used as control
Ig. In the T cell:DC cultures, T cells were resuspended at the end of
the primary 48-h stimulation period and transferred to an uncoated
6-well tissue culture plate (Costar), and 1 ml of fresh media was
added. Plastic adherent DC were not transferred to 6-well plates. Seven
days after the initial stimulation (5 days after cells were transferred
to 6-well plates), the T cells were counted and restimulated with fresh
DC and cytokines/neutralizing mAb for 48 h in 24-well plates
(Costar) that had been coated with human OKT3 in PBS. ELISAs were
performed on culture supernatants harvested from the second
stimulation. ELISAs
mAb pairs (PharMingen) were used in sandwich ELISAs to measure
IL-1ß (sensitivity 100 pg/ml), IL-6 (sensitivity 200 pg/ml), IFN-
(sensitivity 400 pg/ml), p40 IL-12 (sensitivity 100 pg/ml), and p35/p40
(p70) IL-12 (sensitivity 100 pg/ml). MaxiSorp 96-well plates (Nunc,
Naperville, IL) were coated with capture mAbs (1–4 ng/ml) overnight at
4°C. The following day plates were washed and blocked with 3% BSA in
PBS at room temperature for 2 h. Plates were subsequently washed,
and duplicate wells of both standards and samples were added to wells
and incubated overnight at 4°C. Biotinylated secondary mAb (1–3
µg/ml), avidin-peroxidase (Sigma), and
2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (Sigma) were used
to quantify cytokine, as per the PharMingen protocol. Exogenous type I
IFNs were not found to inhibit detection of cytokine in any of the
ELISAs.
Statistical analysis
A one-way ANOVA was used to examine for significant effects of culture conditions on cell cytokine secretion. Variation among culture conditions was examined with a Fisher protected least-significant difference (PLSD) test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously described a human Th cell differentiation model
system in which naive Th cells stimulated with anti-CD3 mAb and
monocyte-derived DC differentiate into IFN--secreting Th cells
(4). In this model, the generation of IFN- secreting Th
cells is completely dependent on the presence of IL-12, indicating that
these cells are indeed derived de novo from the naive Th cells, and not
the result of expansion of any contaminating IFN--secreting memory
Th cells, whose secretion of IFN- is IL-12 independent. We also
found that in this model system the addition of IFN-ß prevents the
generation of IFN--secreting Th cells by inhibiting DC IL-12
secretion, since addition of exogenous IL-12 restores the generation of
IFN--secreting Th cells in the presence of IFN-ß (4).
The CD40L/CD40 accessory pathway is reported to be involved in T
cell-dependent IL-12 secretion by DC (7). Therefore, we
considered that IFN-ß may inhibit DC IL-12 secretion through its
effects on the CD40L/CD40-signaling pathway. To test this idea, we
first addressed whether or not DC IL-12 secretion in our Th cell
differentiation model was, indeed, dependent on the interaction of T
cell-expressed CD40L with CD40 expressed on the DC. This was done by
stimulating cells in the presence or absence of blocking anti-CD40L
mAb, and then assaying 48-h culture supernatants for p40 IL-12 by
ELISA. The amount of secreted p70 IL-12 was not directly assayed
because it is below the level of detection of our ELISA (see Ref.
4 ; data not shown). It should be noted, however, that in
this Th cell differentiation model, production of IFN- by the Th
cells is directly correlated with levels of secreted p40 IL-12, and
neutralizing anti-p70 IL-12 Abs can completely block the generation
of IFN--secreting Th cells (4). The data shown in Fig. 1
demonstrate that anti-CD40L mAb significantly blocks p40 IL-12
secretion in the primary stimulation by more than 75% (Fig. 1). Thus, the CD40L/CD40 pathway appears
to be the predominant pathway by which DC are induced to secrete IL-12
in our Th cell differentiation model.
IFN-ß inhibits CD40-mediated IL-12 secretion by DC
The above experiments led us to hypothesize that IFN-ß may
inhibit the generation of IFN--secreting Th cells by directly
inhibiting CD40-mediated signaling, leading to DC IL-12 secretion. To
examine this hypothesis, we developed a T cell-independent model of DC
activation by cross-linking with anti-CD40 mAb in the absence of Th
cells. The DC themselves did not express sufficient levels of Fc
receptors to perform this cross-linking (data not shown). Consequently,
human FcRII (CD32)-transfected L cells (CD32 Tx L cells) were used
to cross-link anti-CD40 mAb bound to DC. The results, depicted in
Fig. 2, show that CD40 cross-linking
stimulates significant levels of p40 IL-12 secretion by DC, and that
this secretion can be significantly inhibited by IFN-ß. IFN-ß added
to mature DC in these studies did not alter the levels of CD40
expression on the DC (data not shown). Thus, IFN-ß affects
CD40-mediated signaling in DC so as to inhibit secretion of p40
IL-12.
CD40-mediated IL-6 secretion by DC is not inhibited by IFN-ß
IL-6 is a proinflammatory cytokine that has been reported to be
induced by CD40 signaling in DC (12). We analyzed the
effect of IFN-ß on secretion of IL-6 in our Th cell differentiation
model. Naive Th cells were stimulated, in the continued presence or
absence of IFN-ß, with anti-CD3 mAb and DC, and then restimulated
after 7 days. The results show that these stimulation conditions induce
significant levels of IL-6 secretion, which is not affected by
coculture with IFN-ß (Fig. 3A). Simultaneous analysis of
culture supernatants for p40 IL-12 indicated that IFN-ß did inhibit
p40 IL-12 secretion (Fig. 3B), as reported previously
(4).
These results raised the possibility that if CD40 signaling mediates DC
IL-6 secretion, then IFN-ß may differentially regulate CD40-signaling
pathways involved in the induction of cytokine expression. To determine
whether this might be the case, experiments were performed to determine
the involvement of the CD40L/CD40 accessory pathway on the secretion of
IL-6 in our Th cell-dependent model. The results demonstrate that IL-6
secretion during the primary stimulation is significantly inhibited by
anti-CD40L mAb (>75% inhibition; Fig. 4). Thus, the CD40L/CD40 pathway appears
to be the predominant pathway by which DC are induced to secrete both
the cytokines IL-6 and p40 IL-12 in our Th cell differentiation
model.
IFN-ß synergizes with CD40-mediated signaling to induce IL-6 secretion by DC
The above findings indicate that in our Th cell differentiation model, while both IL-6 and p40 IL-12 secretion are dependent on the CD40L/CD40 accessory pathway, IFN-ß inhibits only CD40-induced p40 IL-12. IL-6 can be secreted by both Th cells and DC. Thus, we considered that the contrasting effects of IFN-ß on the secretion of IL-6 and p40 IL-12 might be due to the fact that Th cells may secrete IL-6 in a CD40L-dependent manner, and IFN-ß only effects CD40 signaling in the DC. To address this possibility, we used our Th cell-free model of DC activation to determine the effects of CD40 signaling on DC IL-6 secretion in the presence or absence of IFN-ß.
In these studies, culture supernatants were collected 48 h after
stimulation of the DC with anti-CD40 mAb, and the amount of IL-6 in
the supernatant was determined by ELISA. The results shown in Fig. 5 indicate that neither anti-CD40 mAb
cross-linking of DC nor culture of DC with IFN-ß alone could lead to
IL-6 secretion. Strikingly, however, the combined effects of
anti-CD40 mAb cross-linking and IFN-ß could induce significant
IL-6 secretion by the DC. These results indicate that IFN-ß strongly
synergizes with CD40-mediated signals to induce secretion of IL-6 by DC
and demonstrate that IFN-ß differentially regulates CD40-induced, DC
p40 IL-12, and IL-6 cytokine secretion.
LPS-induced IL-6 and IL-12 by DC is not affected by IFN-ß
To further characterize the mechanisms(s) by which IFN-ß
inhibits IL-12 secretion, we extended our studies to determine whether
the capacity of IFN-ß to inhibit CD40-induced p40 IL-12 secretion by
DC has broader implications for other, CD40-independent pathways that
are capable of inducing DC IL-12 secretion. One such pathway is that
activated by LPS-induced stimulation of DC. Activation by LPS leads to
DC cytokine secretion of both IL-12 and IL-6. We tested the effects of
IFN-ß on LPS-induced DC activation leading to p40 IL-12 and IL-6
secretion. In these studies, DC were stimulated, in the absence of Th
cells, with LPS in the presence or absence of IFN-ß, and 48 h
after stimulation the culture supernatant was collected and cytokine
levels were determined by ELISA. The results show that LPS-induced p40
IL-12 (Fig. 6A) and IL-6 (Fig. 6B) secretion by DC. Addition of IFN-ß to DC cultures with
LPS did not significantly affect the levels of p40 IL-12 (Fig. 6A) and IL-6 (Fig. 6B) secretion by DC.
Dose-response experiments with lower concentrations of LPS and/or
higher levels of IFN-ß did not alter the basic findings presented in
Fig. 6 (data not shown). These results suggest that the effects of
IFN-ß on DC IL-12 secretion may be limited to the CD40-signaling
pathway.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and -ß, could inhibit DC
expression of IL-12 and, as a consequence, prevent priming of naive
CD4+ T cells for IFN- secretion
(4). The ability of type I IFNs to block IFN- secretion
was shown to be entirely due to inhibition of IL-12, since the addition
of exogenous IL-12 restored T cell IFN- production (4).
The main goal of this study was to ascertain the mechanism(s) by which
IFN-ß prevents IL-12 secretion by DC. We identified the CD40L/CD40
accessory pathway as the target for the IFN-ß-mediated inhibition of
T cell-dependent DC IL-12 secretion (Fig. 2). We also established that
the effect of IFN-ß on CD40-mediated induction of IL-12 was not due
to its inhibition of all CD40-signaling pathways; IFN-ß was found to
augment CD40-dependent IL-6 secretion by DC (Fig. 5). In addition, the
finding that LPS-induced p40 IL-12 secretion was not affected by
IFN-ß demonstrated that IFN-ß does not inhibit all DC pathways
leading to IL-12 secretion (Fig. 6A). Similarly, IFN-ß did
not augment IL-6 secretion in a generalized manner since LPS-induced
IL-6 secretion by DC was not affected by this type I IFN (Fig. 6B). Our data in the human confirm and extend earlier data
from Cousens et al. (13), who showed in a mouse model of
viral infection that type I IFNs inhibited secretion of IL-12 but not
IL-6 during infection. However, in contrast to our findings, in their
in vivo viral model, LPS-induced IL-12 secretion was also inhibited by
type I IFNs. This latter difference may reflect a species-dependent
variation in response to LPS or type I IFNs, but may more likely be due
to differences between our in vitro model which focuses only on the
LPS-induced response of monocyte-derived DCs, and their in vivo model
in which multiple cell types may be involved in an LPS response.
IFN-ß appears to inhibit DC p40 IL-12 secretion more completely when
the DC are stimulated in our Th cell differentiation model (Fig. 3B) than when they are activated in a T cell-free model with
CD40 mAb (Fig. 2). There are several factors which might be considered
to contribute to this finding. IFN-ß may directly affect T cells in
the Th cell differentiation model in such a way as to inhibit DC IL-12
secretion. For example, we have found that IFN-ß induces secretion of
IL-10 by T cells in this model, and IL-10 has been reported by others
to be able to inhibit IL-12 (4, 7). We have, however,
previously shown that IL-10 is not a significant factor in the
inhibition of IL-12 by IFN-ß (4). We also considered
that IFN-ß might lower T cell expression of CD40L but, similarly,
this was not be observed in flow cytometric analysis of T cell surface
CD40L (data not shown). We have previously reported that IFN-ß
influences Th cell differentiation and function independently from its
effects on the DC, and, thus, it is possible that IFN-ß may effect T
cell function in a manner, as yet unrecognized, that might influence DC
IL-12 secretion (14). We believe, however, that the most
likely cause for the differences observed in the blocking effect of
IFN-ß between these two model systems is simply that p40 IL-12
secretion in the Th cell differentiation model was determined with much
fewer DC cells present in the culture when compared with experiments in
the anti-CD40 mAb-dependent model (10-fold less).
IFN-ß strongly synergized with anti-CD40 mAb to induce DC IL-6
secretion (Fig. 5), while inhibiting p40 IL-12 secretion (Fig. 2),
indicating that IFN-ß differentially regulates CD40-mediated
signaling in DC. A similar synergy in inducing IL-6 secretion was not
observed when IFN-ß was added to the model system with
CD4+ T cells and DC (Fig. 3A), and the
basis for this difference between the two models is not known. It is
possible that in the Th cell model IFN-ß may have effects on other
regulatory pathways that modulate IL-6 secretion. For example, IL-10,
which is induced by IFN-ß, is known to inhibit a number of DC
functions, and this inhibition is reported to extend to IL-6 secretion
(15). Alternatively, IFN-ß and IFN- are known to have
some overlapping effects on DC functions (e.g., induction of DC class I
expression) and to have the activation of certain signaling pathways in
common (e.g., Jak1 activation (16)), and it is possible
that both IFN-ß and IFN- may activate a signaling pathway that
induces IL-6 secretion in DC. If this were the case, addition of
IFN-ß to the Th cell differentiation model might be expected to
result in a concomitant loss in IFN--dependent IL-6 secretion and an
increase in IFN-ß-induced IL-6. Finally, it is possible that Th
cell-secreted IL-6 may contribute significantly to the total levels of
IL-6 measured in the absence of IFN-ß, but that this Th cell-secreted
IL-6 is inhibited by coculture with IFN-ß. Thus, in all three cases,
the net outcome of these proposed explanations is that similar levels
of IL-6 may be secreted when Th cells and DC are cultured with and
without IFN-ß.
The innate immune response against Gram-negative bacteria predominantly
involves the specific recognition of the glycolipid LPS by specific
cell surface-expressed receptors, including CD14 (17) and
the recently identified Toll-like receptor 2, a new member of the Toll
receptor family (18, 19). Our DC were derived from
elutriated monocytes by culture with GM-CSF, IL-4, and TNF-, a
process that results in the loss of CD14 expression (data not shown).
This implies that LPS recognition in our model may occur through
binding to a Toll receptor family member. LPS stimulates monocytes and
DC to secrete the cytokines IL-6 and IL-12. We found that LPS-induced
IL-6 and p40 IL-12 secretion by our DC, and that this secretion
contrasted with CD40-induced secretion of these cytokines in that it
was not sensitive to the effects of IFN-ß. Although LPS and CD40
cross-linking both induce p40 IL-12 gene expression, they
appear to do so through separate pathways. Engagement of CD40 results
in activation of Jak3, STAT3, and STAT6 in B cells (20, 21), as well as members of the TNFR-associated factor (TRAF)
family of signaling molecules (12). In contrast, LPS has
not been found to affect any STAT or TRAF proteins (22).
In addition, although the same NF-
B binding sites are important for
murine p40 IL-12 promoter activity after stimulation with either LPS or
CD40L, the two signaling pathways have also been shown to activate
different subsets of the NF-B/Rel family of transcription factors;
LPS primarily activates p50/p50 and p50/c-Rel dimers while CD40/CD40L
interaction induces p50/p65 and p50/RelB (23, 24, 25). Thus,
it is possible that IFN-ß may differentially affect signaling
pathways mediating CD40-dependent and LPS-dependent IL-6
gene transcription and, thereby, differentially regulate DC IL-6
secretion.
Although the molecular mechanism whereby type I IFNs regulate p40 IL-12
expression has not been determined, several reports suggest that
IFN-ß regulate gene transcription through their effects on NF-B
activation. Lopez-Collazo et al. (26) found that
IFN-ß inhibit degradation of I-B (inhibitory protein that
dissociated from NF-B) molecules, an event which is necessary for
NF-B activation and translocation to the nucleus. Reports of others
suggest that IFN- inhibits activation of p50/p65 complexes
(27, 28). Thus, IFN-ß-mediated inhibition of
CD40-induced p40 IL-12 could involve a block in p50/p65 complex
activation and/or translocation to the nucleus.
In summary, type I IFNs were found to regulate cytokine secretion by DC-T cell conjugates. The ability of IFN-ß to effectively inhibit CD40-induced DC p40 IL-12 secretion while augmenting Th cell expression of IL-10 (4) suggests that type I IFNs have the potential to inhibit the generation of Th1-like cells. Type I IFNs did not affect LPS-induced p40 IL-12 secretion, and others have shown that these IFNs can up-regulate the high affinity IL-12 receptor on T cells (29). Taken together, these data lead us to speculate that type I IFNs may have differential effects on the generation of Ag-specific Th cell subsets, depending on the origin of the specific Ag. Specifically, type I IFNs may inhibit inflammatory Th1 cell-mediated responses when IL-12 secretion is predominantly dependent on the CD40L/CD40 pathway, such as may be the case in viral immune responses and certain autoimmune responses. In contrast, type I IFNs may promote Th1-like immune responses against Gram-negative, LPS-containing bacteria since, in these instances, inhibition of IL-12 secretion would not be expected to occur, and the expression of high-affinity IL-12 receptors on Th cells may be augmented. Thus, the inhibitory effect of IFN-ß on CD40L/CD40-dependent IL-12 secretion may, at least in part, be an explanation for the beneficial effects of IFN-ß in the treatment of patients with multiple sclerosis (30).
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Acknowledgments |
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Footnotes |
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2 Current address: BASF Bioresearch, 100 Research Drive, Worcester, MA 01605.
3 Address correspondence and reprint requests to Dr. Gijs A. van Seventer, Committee on Immunology and Department of Pathology, Division of Biological Sciences, University of Chicago, 5841 South Maryland Avenue, Room J541A, MC1089, Chicago, IL 60637-1463. E-mail address:
4 Abbreviations used in this paper: DC, dendritic cell; PLSD, protected least-significant difference.
Received for publication June 21, 1999. Accepted for publication October 8, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-producing by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J. Exp. Med. 178:1041./ß inhibition of interleukin 12 and interferon- production in vitro and endogenously during viral infection. Proc. Natl. Acad. Sci. USA 94:634.B half-site. Mol. Cell. Biol. 15:5258.[Abstract]
B. Eur. J.
Immunol. 3461.
B/Rel proteins. Mol. Cell. Biol. 18:5523.ß attenuates the expression of inducible nitric oxide synthase through a decrease in NF-B activation. J. Immunol. 160:2889. inhibits the murine cytomegalovirus immediate-early gene expression by down-regulating NF-B activity. Virology 211:251.[Medline]
and IFN- on phosphorylation of p65 and p50 (rel) in the K562 cell line: implications for altered interaction with RXR ß. Cytokine 8:357.[Medline]
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R. B. Mailliard, Y.-I. Son, R. Redlinger, P. T. Coates, A. Giermasz, P. A. Morel, W. J. Storkus, and P. Kalinski Dendritic Cells Mediate NK Cell Help for Th1 and CTL Responses: Two-Signal Requirement for the Induction of NK Cell Helper Function J. Immunol., September 1, 2003; 171(5): 2366 - 2373. [Abstract] [Full Text] [PDF]
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R. T. Semnani, A. Y. Liu, H. Sabzevari, J. Kubofcik, J. Zhou, J. K. Gilden, and T. B. Nutman Brugia malayi Microfilariae Induce Cell Death in Human Dendritic Cells, Inhibit Their Ability to Make IL-12 and IL-10, and Reduce Their Capacity to Activate CD4+ T Cells J. Immunol., August 15, 2003; 171(4): 1950 - 1960. [Abstract] [Full Text] [PDF]
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B. Nardelli, L. Zaritskaya, M. Semenuk, Y. H. Cho, D. W. LaFleur, D. Shah, S. Ullrich, G. Girolomoni, C. Albanesi, and P. A. Moore Regulatory Effect of IFN-{kappa}, A Novel Type I IFN, On Cytokine Production by Cells of the Innate Immune System J. Immunol., November 1, 2002; 169(9): 4822 - 4830. [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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C. Natarajan and J. J. Bright Curcumin Inhibits Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through Janus Kinase-STAT Pathway in T Lymphocytes J. Immunol., June 15, 2002; 168(12): 6506 - 6513. [Abstract] [Full Text] [PDF]
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Z. Trobonjaca, A. Kroger, D. Stober, F. Leithauser, P. Moller, H. Hauser, R. Schirmbeck, and J. Reimann Activating Immunity in the Liver. II. IFN-{beta} Attenuates NK Cell-Dependent Liver Injury Triggered by Liver NKT Cell Activation J. Immunol., April 15, 2002; 168(8): 3763 - 3770. [Abstract] [Full Text] [PDF]
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S. Masli, B. Turpie, K. H. Hecker, and J. W. Streilein Expression of Thrombospondin in TGF{beta}-Treated APCs and Its Relevance to Their Immune Deviation-Promoting Properties J. Immunol., March 1, 2002; 168(5): 2264 - 2273. [Abstract] [Full Text] [PDF]
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 R. T. Semnani, H. Sabzevari, R. Iyer, and T. B. Nutman Filarial Antigens Impair the Function of Human Dendritic Cells during Differentiation Infect. Immun., September 1, 2001; 69(9): 5813 - 5822. [Abstract] [Full Text] [PDF]
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A. E. Morelli, A. F. Zahorchak, A. T. Larregina, B. L. Colvin, A. J. Logar, T. Takayama, L. D. Falo, and A. W. Thomson Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation Blood, September 1, 2001; 98(5): 1512 - 1523. [Abstract] [Full Text] [PDF]
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X. Ma and L. J. Montaner Proinflammatory response and IL-12 expression in HIV-1 infection J. Leukoc. Biol., September 1, 2000; 68(3): 383 - 390. [Abstract] [Full Text] [PDF]
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B. L. McRae, T. Nagai, R. T. Semnani, J. M. van Seventer, and G. A. van Seventer Interferon-alpha and -beta inhibit the in vitro differentiation of immunocompetent human dendritic cells from CD14+ precursors Blood, July 1, 2000; 96(1): 210 - 217. [Abstract] [Full Text] [PDF]
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