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* Department of Dermatology and
Institute of Clinical Microbiology, Immunology, and Hygiene, University of Erlangen-Nuremberg, Erlangen, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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or CD40. The IL-4R signaling for DC maturation requires the IL-4R
-chain and STAT6, but not Janus kinase 3, indicating that IL-4R type
II signaling is preferentially responsible for these effects. In
contrast, the production of IL-12 p70, but not IL-10 and TNF, induced
by microbial products was enhanced only by IL-4, not by IL-13 or Y119D,
a selective type II IL-4R agonist, in vitro and in vivo. This
enhancement was dependent on the presence of Janus kinase 3, indicating
that this function is exclusively mediated by the type I IL-4R. In
short, we discerned the individual roles of the two IL-4R types on DC
function, showing that IL-4R type I promotes IL-12 secretion
independently of GM-CSF concentration, while IL-4R type II promotes the
up-regulation of MHC class II and costimulatory surface markers in a
GM-CSF concentration-dependent manner. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-4 exerts its actions on immune cells using two types of receptors.
The type I heterodimer consists of the IL-4R -chain (IL-4R) in
association with the common cytokine receptor 
-chain
(c), while the type II receptor is comprised of the
IL-4R in association with the IL-13R1. While B cells,
macrophages, and mast cells express both IL-4R types I and II, T cells
express only IL-4R type I. IL-4 is able to bind both receptors, while
IL-13 signaling is restricted to IL-4R type II
(11, 12, 13, 14).
Little information is available on the expression of the two types of
IL-4R on DC and which DC functions might be affected by IL-4 or IL-13.
Mature murine DC express c and functionally use it for
IL-4R type I signaling, as anti-c mAb could affect
IL-4 signaling (15). In contrast, IL-4 and IL-13 resulted
in strong activation of STAT6 via the IL-4R of both type I and II
receptors in mature BM-DC generated with high doses of GM-CSF
(16). Recently, the role of IL-4 as a Th1-directing
cytokine was strengthened by the observation that IL-12 p70 production
by DC is increased by IL-4 (17).
Here the expression and function of IL-4R types I and II and their
associated molecules STAT-6 and Janus kinase 3 (JAK3) were addressed in
murine BM-DC generated with different doses of GM-CSF and using the
respective knockout mice. We show that IL-4- and IL-13-mediated
phenotypical maturation of DC occurs mainly via IL-4R type II and is
dependent on IL-4R/STAT-6 signaling. In contrast, enhancement of
IL-12 production by DC occurs exclusively via IL-4R type I and is
dependent on JAK3.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The preparation and culture of BM cells from C57BL/6 and BALB/c
mice to generate DC has been previously described (7).
GM-CSF (PeproTech/Tebu, Frankfurt, Germany) was used at low (5 U/ml) or
standard (200 U/ml) concentrations. IL-4R-/-
mice were provided by F. Brombacher (University of Cape Town, Cape
Town, South Africa), and STAT4-/-,
STAT6-/-, and JAK3-/-
mice were purchased from J. Ihle (St. Jude Children’s Research
Hospital, Memphis, TN).
Cytokines and IL-4R agonists/antagonists
rIL-4 and rIL-13 (purchased from PeproTech) were used at standard doses (100 U/ml) or high doses (500 U/ml). Mutated mouse IL-4 (IL-4.Y119D) was generated as described recently (18) by expression in transfected human embryonic kidney cells (293 EBNA; Invitrogen, Groningen, The Netherlands) and subsequent purification by affinity chromatography.
RNA isolation and RT-PCR
After RNA extraction from DC populations with acidic guanidinium
thiocyanate, cDNA was synthesized for each time point in 20-µl
reactions containing 1 µg total RNA, 50 mM Tris-HCl (pH 8.3), 5 mM
MgCl2, 1 mM of each dNTP, 2.5 mM oligo(dT), 32 U
RNAguard, and 17 U avian myeloblastosis virus reverse
transcriptase (all from Amersham Pharmacia Biotech, Freiburg, Germany)
at 42°C for 90 min. The cDNA was amplified in a 40-µl reaction
volume containing 50 mM Tris-HCl (pH 8.3), 2.5 mM
MgCl2, 10 mM of each dNTP, 1 U Taq
polymerase (Pharmacia Biotech, Piscataway, NJ), and 100 nM primers
during 35 cycles (1 min denaturation at 94°C, 1 min annealing at
58–63°C, 1 min extension at 72°C). Samples were analyzed on 2%
agarose gels containing 0.2 µg/ml ethidium bromide. The primers used
were as follows: IL-4R sense primer,
5'-GGCCTGGCAGTGGCATGGGAGGCC-3'; IL-4R antisense primer,
5'-TTATCGTGCCCGCTGGGGCCCTGC-3' (amplified fragment of 273 bp);
IL-13R sense primer, 5'-ACAGAAGTTCAGCCACCTGTGACG-3'; IL-13R antisense
primer, 5'-ACACTTCATATAGCTCAGCTTATGCCA-3' (amplified fragment of 348
bp); 
-actin sense primer, 5'-CACCCGCCACCAGTTCGCCA-3'; -actin
antisense primer, 5'-CAGGTCCCGGCCAGCCAGGT-3' (amplified fragment
of 574 bp); c sense primer,
5'-CCCAGAGAAAGAAGAGCAAGCACC-3'; and c antisense primer,
5'- GGGGTCCTGGAGCTGGACAACAAA-3' (amplified fragment of 429
bp).
FACS analysis
FACS analysis was performed as previously described (7). One to 5 x 105 BM-DC were stained directly with PE-conjugated mAb directed against MHC class II (M5/114), or FITC-conjugated B7-2 (GL1), CD14, and CD40 (3/23; all from BD PharMingen, Hamburg, Germany), TNFR1, TNFR2 (Serotec, Oxford, U.K.), or the appropriate fluorochrome-conjugated isotype control mAb at 2–5 µg/ml in PBS containing 0.1% sodium azide and 5% FCS for 30 min on ice in the dark. Samples were washed once in staining buffer and subsequently measured and analyzed with a FACScan (BD Biosciences, Heidelberg, Germany).
ELISA
BM-DC were taken on day 8 of culture, and 1 x
106 cells/well were transferred to a 24-well
plate (Falcon; BD Biosciences) with 10 µg/ml fixed
Staphylococcus aureus Cowan I strain (SAC; Pansorbin,
Calbiochem, Bad Soden, Germany) with or without 100 U/ml IFN- (BD
PharMingen). After 24 h cell supernatants were collected and
tested for IL-12 p70, IL-12 p40, TNF-, and IL-10 production with BD
OptEIA Kits (BD PharMingen) according to the manufacturer’s
instructions.
In vivo cytokine induction
We used the protocol as previously published by Hochrein et al. (17). BALB/c mice or STAT6-deficient BALB/c mice were administered LPS (10 µg) with or without the addition of IL-4, IL-4Y119D, or IL-13 (1 µg) via i.p. injection. These reagents were administered in PBS containing 1% FCS. Control mice received i.p. injections of PBS/FCS alone. Mice were killed after 4 h, blood was taken, and serum was collected for IL-12 assay by ELISA.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have shown previously that the generation of large numbers of
mature BM-DC can be achieved by GM-CSF alone (7). Here we
show that the generation of mature BM-DC using standard doses of GM-CSF
(200 U/ml) cannot be further improved phenotypically or functionally by
adding standard doses of IL-4 (100 U/ml) to the cultures. The
proportions of mature DC represented by high surface expression of MHC
class II (MHC II) and CD86 (Fig. 1
a) as well as CD80, CD40, and
CD54 (data not shown) (7) remained unaltered in cultures
with or without standard doses of IL-4. This was observed throughout
with different inbred mouse strains (C57BL/6, BALB/c, FVB), and the
mean percentages of mature DC (MHC IIhigh and
CD86+) within the cultures of 16 independent
experiments after 8–10 days are shown (Fig. 1b). These
similar surface phenotypes correlated with their capacity to stimulate
allogeneic MLR in vitro and were not influenced by further DC
prestimulation with TNF- (Fig. 1c).
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When low doses of GM-CSF (5 U/ml) were used for BM-DC generation
(LowGM-DC), only immature DC develop, characterized by the low
expression of MHC II molecules, with few or no costimulatory molecules
(Fig. 2, a and b)
(10). Similarly, DC generated from
STAT6-/- mice did not respond to IL-4 and
remained immature (Fig. 2c). In contrast, control BM-DC
generated from unrelated STAT4-/- or wild-type
mice readily matured.
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b) and IL-4.Y119D (data not shown), a specific
agonist for IL-4R type II (18), were equally potent in
mediating DC maturation. Also JAK3-deficient (IL-4R type I) DC readily
matured in the presence of IL-4 (Fig. 2c), indicating that
IL-4 signaling via c is not involved in DC maturation.
Thus, although IL-4R signaling via STAT-6 is shared by both IL-4R,
these data point to the type II receptor as the primary signaling
pathway for this maturation enabled by IL-4 and IL-13.
To prove that all the different components of the IL-4R complexes are
expressed by the different DC, we performed RT-PCR with RNA from BM-DC
generated from C57BL/6 mice in the presence of low or high
concentrations of GM-CSF with or without IL-4. As shown in Fig. 2d, the mRNAs for the IL-4R, c, and
IL-13R1 could be detected under all four culture conditions. The
same results were achieved by analyzing BM-DC derived from
c-deficient (with the exception of the -chain) and
JAK3-deficient mice (data not shown).
IL-4 signaling reverts the maturation resistance of DC at low doses
of GM-CSF by combined treatment with IL-4 and TNF-
Previous results indicated that immature LowGM-DC are resistant to
maturation stimuli such as TNF- (10). We therefore
investigated whether the addition of IL-4- to TNF--treated LowGM-DC
might be able to convert this maturation-resistant state. Indeed, the
combined treatment of LowGM-DC cultures on day 8 with IL-4 and TNF-
for an additional 5 days, but not with each of the cytokines alone,
resulted in DC maturation (Fig. 3). These
findings raised the question of whether IL-4 and IL-13 act directly as
a maturation stimulus for DC or whether they enable the responsiveness
of DC to TNF- (see below).
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IL-4 treatment to promote BM-DC maturation at low doses of GM-CSF
depends on IL-4R and STAT6 signaling. Likewise, GM-CSF can activate
STAT6 in murine BM-DC (16) (our own observations; data not
shown). However, mature DC develop normally from STAT-6-deficient BM
cells with high doses of GM-CSF (data not shown), indicating clearly
that in this case STAT-6 is not involved in the promotion of DC
maturation.
To test whether the effects of IL-4 on DC maturation are dependent on
an absolute or a relative amount of GM-CSF in relation to IL-4, BM-DC
were generated with standard doses of GM-CSF (200 U/ml) until day 8,
and increased concentrations of IL-4 (high dose; 500 U/ml) were added
for 24 h alone or together with different maturation stimuli (Fig. 4). Such high doses of IL-4 were able to
increase the number of mature DC in the cultures from 20 to 35% (Fig. 4). Weaker stimuli, such as TNF- and CD40 ligation, acted
synergistically together with IL-4 to further promote DC maturation up
to 64%, whereas stronger stimuli, such as LPS or SAC alone,
efficiently induced maximal maturation and thus showed little
additional effect in combination with IL-4 (Fig. 4). These data
indicate that an effect of IL-4 on DC maturation can only be observed
when the doses of IL-4 are relatively higher than the doses of GM-CSF
in the cultures.
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Because IL-4 and IL-13 augmented TNF--, anti-CD40-, and
LPS-induced DC maturation at relatively low doses of GM-CSF (Figs. 3 and 4), we investigated whether IL-4 and IL-13 influence the expression
of the respective surface receptors used by these maturation stimuli.
IL-4 only induced CD40 expression, but down-regulated TNFR2 and CD14
(Fig. 5). In contrast, IL-13 had no
influence on CD40 and CD14 expression, but slightly up-regulated TNFR2
(Fig. 5). These data argue for direct effects of IL-4R-mediated signals
on DC maturation, rather than indirect effects by induction of other
maturation-inducing receptors. Furthermore, the different effects of
IL-4 and IL-13 are indicative of distinct functions for IL-4R types I
and II on DC, respectively.
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Besides the up-regulation of MHC II and costimulatory molecules on
the surface of DC, the production of IL-12 is a major feature of DC
maturation (9, 19). IL-4 was recently shown to enhance
bacteria-induced IL-12 p70, but not IL-12 p40, production by human and
murine DC (17). We have now extended these studies in an
attempt to unravel the IL-4R signaling pathway responsible for the
enhanced IL-12 production of DC by also applying IL-13 and generating
BM-DC from JAK3-/- and
STAT6-/- mice. BM-DC were stimulated with SAC
with or without IFN- to produce IL-12 p70, and the additional effect
of IL-4 or IL-13 on DC cytokine production was investigated. In
wild-type mice IL-4 doubled the amount of IL-12 p70 produced, while
IL-13 had no effect. In addition, the enhancing effect of IL-4 was
abrogated in JAK3-/- and
STAT6-/- mice (Fig. 6a). IL-4 and IL-13 did not
induce IL-12 by themselves (not shown) and did not influence IL-12 p40
(Fig. 6a), IL-10, or TNF- production (Fig. 6b). To test whether the type II receptor is functional on
mature DC, we analyzed IL-13-induced activation of STAT-6. Because
STAT-6 was found to be tyrosine phosphorylated in response to IL-13 to
a similar extent as in IL-4-treated DC (data not shown), the type II
IL-4R is functional, but not involved in IL-12 induction.
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c) or the type II IL-4R agonist IL-4.Y119D. These
data point to IL-4R type I as the only receptor involved in the
enhancement of IL-12 p70 production. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and CD40
ligation. To date, maturation resistance of DC has been described only
for this LowGM-DC (10) and for 1,25-dihydroxyvitamin
D3-treated DC (22). Maturation
resistance is advantageous for tolerance induction in vivo, as such DC
remain immature after injection and are thus more effective in
tolerance induction. It is consequently important to understand the
mechanisms underlying such a resistance to maturation of DC.
Previously, we observed that the presence of IL-4 throughout the
LowGM-DC culture could reverse the immature maturation-resistant state
(10). Here we found, in addition, that the resistance to
maturation via stimuli such as TNF, LPS, and anti-CD40 of already
established LowGM-DC cultures can be reversed by IL-4 (Fig. 3) and
IL-13 (not shown). This shows that IL-4 and IL-13 are critically
involved in regulation of the maturation-resistant state of DC.
However, the molecular details of maturation resistance remained
unresolved.
One possibility is that IL-4 and IL-13 may up-regulate the expression
of receptors for DC maturation stimuli, such as TNFR, CD40, or the LPS
coreceptor CD14. It has been shown that TNF- can be produced
endogenously by adherent macrophages in BM-DC cultures
(23), and IL-4/IL-13 cooperate with TNF- on blood
mononuclear cells (24), which also contain precursors for
DC. Thus, IL-4 might play a role as an enhancer of the sensitivity of
DC to maturation stimuli such as TNF- in situations where GM-CSF is
limited, rather than as a direct activator of DC maturation. Although
IL-4 and IL-13 induced maturation of LowGM-DC equally well, their
effects on TNFR were completely different. TNFR2 was down-regulated by
IL-4 and slightly up-regulated by IL-13. This argues for direct effects
by the IL-4 and IL-13 receptor subtypes not involving
regulation of the two TNFRs. Also, CD40 and the LPS coreceptor
CD14 were differentially influenced by IL-4 or IL-13, which, therefore,
could not explain the similar maturation-inducing capacity of the two
cytokines.
As maturation effects on DC by IL-4 and IL-13 are only detectable when
the doses of GM-CSF are relatively lower than the doses of IL-4/IL-13
(i.e., 5 U/ml LowGM conditions and 100 U/ml IL-4 (Fig. 2) or standard
doses of 200 U/ml GM-CSF and 500 U/ml IL-4 (Fig. 4), but not 200 U/ml
GM-CSF and 100 U/ml IL-4 (Fig. 1)), these cytokines might compete for a
common signaling pathway. It has been shown that GM-CSF can activate a
panel of STAT molecules, including STAT6 (16) (our
unpublished observations); therefore, GM-CSF and IL-4/IL-13 may
cooperate in activating STAT6. When GM-CSF is limited, the insufficient
STAT6 activation could be compensated for by IL-4 or IL-13. In
contrast, at high doses of GM-CSF, STAT6 activation may be sufficient
to sensitize for other maturation stimuli, such as TNF-. Thus, the
dual effect of low doses of GM-CSF in the absence of IL-4 might
decrease STAT6 activation to amounts that render immature DC unable to
respond to other maturation stimuli. This topic is currently under
further investigation.
Several recent studies indicate that the effects of IL-4 on DC observed here in vitro might be of relevance in experimental and pathological situations in mice and humans. Unexpectedly, in vivo studies with IL-4-deficient mice showed that IL-4 is essential during the priming phase of Th1 or CTL immune responses (25, 26). Injections of blocking anti-IL-4 Abs prevented allogeneic T cell priming in vivo (27). Also, anti-tumor responses improve in vivo when initiated by BM-DC grown at intermediate doses of GM-CSF in the presence of IL-4 (28) or when GM-CSF is overexpressed in DC (29, 30). The Th1-inducing capacity of IL-4 observed in vivo is not likely to be mediated by direct effects on naive CD4+ T cells, because IL-4 inhibits Th1 development by suppression of IL-12R expression (10, 11, 12). Thus, the Th1-inducing effect of IL-4 during the priming phase may well be dependent on DC. Recent reports indicate that the time point of IL-4 action importantly influences Th2 or Th1 outcome. When IL-4 is coadministered with an Ag at the site of DC encounter in vivo, IL-4 clearly promoted IL-12 production by DC and their Th1-driving potential (31, 32).
This indirect Th1-inducing effect of IL-4 via DC could account for the
IL-4-mediated disease aggravation in some acute, but not chronic,
phases of several diseases, such as atopic dermatitis
(33), asthma (34), hepatitis
(35), graft-vs-host disease (36), or
allograft rejection (37, 38). Furthermore, there is
evidence that such IL-4-mediated sensitization in vivo is mediated via
STAT6 signaling (39, 40), similar to that observed in our
BM-DC cultures. In acute phases of tissue inflammation, IL-4 and IL-13
may act on the residing DC population, which renders them sensitive to
TNF- stimulation or other inflammatory cytokines. Infiltrating
monocytes might be driven toward DC differentiation (41, 42), and subsequently these DC may induce Th1 immunity
(17). IL-4 effects can be circumvented by increasing
GM-CSF in our BM-DC cultures or possibly in vivo, when high level
GM-CSF expression is found, as described for chronic atopic dermatitis
(29).
To better understand the maturing and Th1-driving mechanisms of IL-4
and/or IL-13 on DC, we studied the role of their respective receptors
on DC. Very little information on the expression and functional
relevance of the two IL-4R complexes on DC is available to date. In
vitro-generated DC have been reported to express the c.
However, the thymic DC compartment in mice deficient for the
c has been shown to be phenotypically and functionally
normal (43). Analyzing the epidermal-derived DC line,
XS52, which retains important functions of epidermal Langerhans
cells, it has been shown that IL-4 induces a rapid up-regulation
of c-Myc mRNA expression, and this IL-4-dependent signaling could be
almost completely blocked by anti-c mAb
(15). On the surface of human monocyte-derived DC, both
types I and II IL-4R are expressed and functional, as IL-4 and IL-13
both promote the generation of DC (2, 8). Analyzing the
expression of IL-13R1 by a novel (not neutralizing) mAb in mouse
lymph nodes led to the finding that follicular DC, but not
interdigitating DC, express this molecule (44). Thus,
depending on the type and maturation stage of DC, these cells might
respond differently to IL-4 and/or IL-13.
Our data indicate that both IL-4R type I and II complexes are expressed
on DC; however, their functional consequences for DC are different. In
common, both IL-4 and IL-13 promote DC maturation when the doses of
GM-CSF are relatively lower than the doses of IL-4 or IL-13 (see
above). This effect on DC maturation requires signaling though STAT6,
but not JAK3, for IL-4 and IL-13, but not GM-CSF, indicating that IL-4
and IL-13 enable DC maturation through STAT6 activation. GM-CSF might
use other STATs for this process, as previously described
(9). Although we could not directly exclude that the
maturation signal occurs through the type II receptor due to a lack of
specific type I receptor agonists, type II receptor antagonists, or
type II receptor-deficient mice, we found strong evidence for the type
I receptor not being involved in this process. First, IL-4 and IL-13
were equally potent in inducing DC maturation (Fig. 2), and no additive
or synergistic effects could be observed by the combination of both
cytokines (data not shown). Second, the DC maturation effect is
maintained in JAK3-/- mice. Third, all other
effects produced by IL-4 (Figs. 5 and 6) were not found with IL-13,
although the type II receptor could have been engaged by IL-4. Fourth,
mature BM-DC develop normally from STAT6-/-
mice with high doses of GM-CSF (not shown). We therefore argue
that IL-4 or IL-13 signaling responsible for DC maturation occurs
exclusively through the type II receptor.
In contrast to the similar DC maturation-inducing capacities of IL-4 and IL-13, the two cytokines displayed different effects on TNFR, CD40, and CD14 expression and IL-12 p70 production by DC.
While IL-4 down-regulated the expression of TNFR2 and CD14, it up-regulated CD40 expression on DC. In contrast, IL-13 resulted in enhanced TNFR2 levels, but had no influence on CD40 and CD14 expression. This argues for distinct receptors or signaling pathways being used by each cytokine, but does not explain the reversion of maturation resistance by DC. Most likely, other mechanisms triggered similarly by both IL-4 and IL-13 through the type II receptor might be responsible for the induction of DC maturation.
The enhancing effect of IL-4 on IL-12 p70 production by DC has been
described previously (17). Here we show that this effect
could not be achieved through the type II receptor with IL-13 or
IL-4.Y119D, a type II IL-4R-selective IL-4 mutant. Furthermore, this
effect is specific for IL-12 p70, as there was no detectable effect on
IL-12 p40, IL-10, or TNF- production by DC.
The type II IL-4R is not expressed on activated or T cells, which raises the question of possible mechanisms of the previously described Th2-driving potential of IL-13 (45). As we found that IL-13 does not support IL-12 p70 production and thereby Th1 immunity, it might instead promote Th2 responses at the level of DC. The differential effects of IL-4 and IL-13 on the induction of IL-12 p70 could then explain why deficient IL-13 signaling resulted in increased Th1 immune responses (46), either by allowing default pathways or by unknown factors mediating Th2 maturation.
Taken together our data indicate that the two known types of IL-4R mediate different DC functions. While the type II IL-4R (preferentially engaged by IL-13) is responsible for the up-regulation of MHC and costimulatory molecules, the type I IL-4R (exclusively engaged by IL-4) costimulates IL-12 p70 production to support Th1 immunity. It will be of great interest to determine the expression of the different cytokine receptor molecules and their regulation at different maturation stages and in different subtypes of DC. In addition, modulation of DC functions with selective type I or type II IL-4R agonist or antagonists may be used in new therapeutic strategies of immune intervention.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Manfred B. Lutz, Department of Dermatology, University of Erlangen-Nuremberg, Hartmannstrasse 14, D-91052 Erlangen, Germany. E-mail address: lutz{at}derma.med.uni-erlangen.de
3 Abbreviations used in this paper: DC, dendritic cell; BM, bone marrow; c, common cytokine receptor -chain; JAK3, Janus kinase 3; SAC, Staphylococcus aureus Cowan I strain; MHC II, MHC class II.
Received for publication December 26, 2001. Accepted for publication July 3, 2002.
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 J. S. Ahn and B. Agrawal IL-4 is more effective than IL-13 for in vitro differentiation of dendritic cells from peripheral blood mononuclear cells Int. Immunol., October 1, 2005; 17(10): 1337 - 1346. [Abstract] [Full Text] [PDF]
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C.-L. Chu and C. A. Lowell The Lyn Tyrosine Kinase Differentially Regulates Dendritic Cell Generation and Maturation J. Immunol., September 1, 2005; 175(5): 2880 - 2889. [Abstract] [Full Text] [PDF]
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L. Pace, C. Pioli, and G. Doria IL-4 Modulation of CD4+CD25+ T Regulatory Cell-Mediated Suppression J. Immunol., June 15, 2005; 174(12): 7645 - 7653. [Abstract] [Full Text] [PDF]
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J. Padilla, E. Daley, A. Chow, K. Robinson, K. Parthasarathi, A. N. J. McKenzie, T. Tschernig, V. P. Kurup, D. D. Donaldson, and G. Grunig IL-13 Regulates the Immune Response to Inhaled Antigens J. Immunol., June 15, 2005; 174(12): 8097 - 8105. [Abstract] [Full Text] [PDF]
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J. Eguchi, N. Kuwashima, M. Hatano, F. Nishimura, J. E. Dusak, W. J. Storkus, and H. Okada IL-4-Transfected Tumor Cell Vaccines Activate Tumor-Infiltrating Dendritic Cells and Promote Type-1 Immunity J. Immunol., June 1, 2005; 174(11): 7194 - 7201. [Abstract] [Full Text] [PDF]
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F. D. Finkelman, M. Yang, C. Perkins, K. Schleifer, A. Sproles, J. Santeliz, J. A. Bernstein, M. E. Rothenberg, S. C. Morris, and M. Wills-Karp Suppressive Effect of IL-4 on IL-13-Induced Genes in Mouse Lung J. Immunol., April 15, 2005; 174(8): 4630 - 4638. [Abstract] [Full Text] [PDF]
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 M. Menges, T. Baumeister, S. Rossner, P. Stoitzner, N. Romani, A. Gessner, and M. B. Lutz IL-4 supports the generation of a dendritic cell subset from murine bone marrow with altered endocytosis capacity J. Leukoc. Biol., April 1, 2005; 77(4): 535 - 543. [Abstract] [Full Text] [PDF]
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J. Zamorano, M. D. Rivas, F. Setien, and M. Perez-G Proteolytic Regulation of Activated STAT6 by Calpains J. Immunol., March 1, 2005; 174(5): 2843 - 2848. [Abstract] [Full Text] [PDF]
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T. Nikolic, M. Bunk, H. A. Drexhage, and P. J. M. Leenen Bone Marrow Precursors of Nonobese Diabetic Mice Develop into Defective Macrophage-Like Dendritic Cells In Vitro J. Immunol., October 1, 2004; 173(7): 4342 - 4351. [Abstract] [Full Text] [PDF]
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Y.-P. Liao, C.-C. Wang, L. H. Butterfield, J. S. Economou, A. Ribas, W. S. Meng, K. S. Iwamoto, and W. H. McBride Ionizing Radiation Affects Human MART-1 Melanoma Antigen Processing and Presentation by Dendritic Cells J. Immunol., August 15, 2004; 173(4): 2462 - 2469. [Abstract] [Full Text] [PDF]
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 K. Brandt, S. Bulfone-Paus, D. C. Foster, and R. Ruckert Interleukin-21 inhibits dendritic cell activation and maturation Blood, December 1, 2003; 102(12): 4090 - 4098. [Abstract] [Full Text] [PDF]
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