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* Department of Experimental Medicine, University of Perugia, Perugia, Italy; and
Ludwig Institute for Cancer Research, Brussels, Belgium
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and CD8+ subtypes. Furthermore, IL-23and IL-12-Ig
exert biological activities on DC that are only in part overlapping.
While both proteins induce IL-12 production from DC, only IL-23-Ig can
act directly on CD8+ DC to promote immunogenic
presentation of an otherwise tolerogenic tumor peptide. In addition,
the in vitro effects of IL-23-Ig did not appear to require IL-12R
2
or to be mediated by the production of IL-12. These data may establish
IL-23 as a novel cytokine with major effects on
APC. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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p19, a molecule structurally related to IL-6, G-CSF, and the p35
subunit of IL-12, is a component of the recently discovered cytokine
IL-23. p19 was identified by searching the databases with a
computationally derived profile of IL-6 (2). p19 was found
to lack biological activity per se and to combine with the p40 subunit
of IL-12. The p19/p40 pair is naturally expressed by activated mouse
and human dendritic cells
(DC)3 and has
biological effects on T cells that are similar to but distinct from
those of IL-12 (2). Recently, the ubiquitous, transgenic
expression of the IL-23 subunit p19 was found to result in multiorgan
inflammation, runting, infertility, and premature death of mice
(3). These activities probably result from interaction of
IL-23 with the IL-12R1 and an additional, novel receptor subunit
(2).
DC play a central role in activating and regulating T cell responses
(4). Activation of DC by a variety of stimuli and
cytokines leads to the secretion of IL-12, which subsequently induces
IFN-
production by NK cells and directs Th1 development
(5, 6, 7). We have recently described autocrine effects of
IL-12 on murine myeloid APC, such as DC and macrophages (8, 9). In particular, IL-12 was found to interact with surface
receptors expressed by the CD8- subset of
splenic DC, resulting in NF-
B-mediated signaling and leading to the
initiation of inflammatory and Th1-promoting actions (8, 10, 11, 12). In this study, using single-chain IL-23-Ig or IL-12-Ig
fusion proteins, we have compared IL-23 and IL-12 for binding to murine
DC and in vitro and in vivo effects mediated by the interaction with
these cells. We found that the two cytokines elicit overlapping
biological activities in DC by signaling through distinct receptor
subunits expressed differentially by distinct DC subsets. These data
add to the function of IL-23 as an initiator and regulator of
T-dependent immunity in the mouse and highlight a potentially important
role of the cytokine in the modulation of accessory cell function.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The cDNA encoding the p19 chain of mouse IL-23 was generated
from resting cells of the macrophage cell line J774 that constitutively
express p19 transcripts (2). The cDNA was amplified with
primers specifying the mature protein-coding region and containing
restriction site sequences (Table I
). The
cDNA encoding the p35 and p40 chains of murine IL-12 were amplified
from plasmid DNA (13) with mutated primers that added
appropriate restriction sites (Table I). The p40 sense mutated primer
introduced a KpnI 15-base sequence just before the start
codon, and the antisense primer introduced a BspEI site just
before the stop codon. For IL-12 p35 as well as IL-23 p19 cDNA, PCR
amplification involved a sense-mutated primer introducing a
BamHI site just after the presumed 22-aa signal peptide
sequence and an antisense-mutated primer introducing a BclI
site just before the stop codon. Linker sequences were synthesized as
sense and antisense oligonucleotides spanning the sequence reported by
Huston et al. (14) encoding the
(Gly4Ser)3 linker and
adjacent sequences between convenient overhanging restriction enzyme
sites in the 3' and 5' ends of the IL-12 or IL-23 subunit cDNA.
Production of IL-23- or IL-12-Ig fusion proteins was further
accomplished by PCR amplification of the region comprising the hinge,
CH2, and CH3 domains of the murine IgG3 isotype heavy chain, using cDNA
from the IgG3 anti-TNP hybridoma C3110 as a template with
appropriate primers (Table I) (15). After amplification,
PCR products and the linker sequence were digested with the appropriate
restriction enzymes and cloned into the pEF-BOS plasmid
(16). Clones with the correct inserts were stably
transfected by the calcium phosphate method into P1.HTR cells, and
supernatants were collected. Fusion proteins were affinity-purified by
means of protein A-Sepharose. A sandwich ELISA was used to quantitate
fusion proteins. The test was based on the use of p40-specific C15.6
and C17.8 mAb (BD PharMingen, San Diego, CA) and therefore detected p40
in both fusion proteins as well as the heterodimeric p35/p40 complex in
the rIL-12 used as a control. Standard ELISA detection of IL-12 p70
involved the use of p70-specific 9A5 mAb (BD PharMingen) and
p40-specific C17.8 mAb.
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Purified samples containing fusion proteins were collected and
stored at -70°C. Samples were concentrated 20- to 30-fold (Centricon
10; Amicon, Beverly, MA), and aliquots containing 10 ng fusion protein
were run on 8% polyacrylamide gels. The primary Ab was p40-specific
C17.8, and the secondary Ab was a sheep anti-rat
peroxidase-conjugated Ab. Blots were developed using a chemiluminescent
technique. Levels of IL-23/IL-12 bioactivity in fusion proteins were
determined using mitogen activation of splenocytes by measuring IFN-
production in response to IL-12 or IL-23 (2). In all in
vitro experiments involving IL-23-Ig or IL-12-Ig, recombinant Ig
protein (rIg) encompassing the Ig portion of the fusion proteins was
used as a control (15). All recombinant proteins,
including heterodimeric IL-12, were used at a concentration of 10 ng/ml
unless otherwise indicated.
DC purification and binding analysis
DC were prepared and fractionated according to CD11c/CD8
expression using positive selection columns in combination with CD11c
and CD8 microbeads (Miltenyi Biotec, Bergisch Gladbach, Germany) as
previously described (17). The DC preparation consisted of
96–98% CD11c+, >99%
Ia+, >98% B7-2+, and
<0.1% CD3+ cells and appeared to consist of
90–95% CD8- and 5–10%
CD8+ cells. After DC fractionation, the recovered
CD8- cells typically contained <0.5%
contaminating CD8+ DC, whereas the
CD8+ fraction was made up of >90%
CD8+ DC.
Flow cytometry was employed to assess the expression of cytokine
receptors in freshly harvested DC or the DC cell line CB1
(8). Typically, 2 x 105 cells
in 100 µl PBS/3% FCS were incubated with 1 µg FITC-conjugated
fusion protein after blocking the FcR on DC by means of 2.4G2 mAb
(9). The stained cells were analyzed on a FACScan (BD
Biosciences, San Jose, CA). To assess the specificity of the IL-12R
staining, labeling was also performed in the presence or the absence of
an excess of free rIL-12. In addition, in selected experiments FACS
staining involved the use of unlabeled fusion proteins as the first
step, followed by PE-labeled polyclonal anti-IgG3 as the
second step.
Skin test assay
A skin test assay was employed for assaying the cytokine adjuvant potential for promotion of class I-restricted delayed-type hypersensitivity to synthetic peptides as previously described (18). Briefly, peptide-loaded DC (3 x 105), treated or not with cytokine/fusion proteins, were transferred into recipient hosts that were assayed for the development of peptide (P815AB)-specific delayed-type hypersensitivity at 2 wk. In selected experiments, a combination of CD8- DC (3 x 105) and CD8+ DC (104) was transferred into recipient hosts (11, 12). To test for possible nonspecific effects of peptide challenge, specificity controls routinely involved the use of the antigenically unrelated P91A peptide, and no effects were found (9, 19). Results were expressed as the increase in footpad weight of peptide-injected footpads over that of vehicle-injected counterparts. Data are the mean ± SD for at least six mice per group. The statistical analysis was performed using Student’s paired t test by comparing the mean weight of experimental footpads with that of control counterparts (19).
Mice and additional reagents
Female DBA/2J mice (H-2d) were obtained
from Charles River Breeding Laboratories (Calco, Milan, Italy) and were
used at the age of 2–4 mo. Murine rIL-12 was a gift from Genetics
Institute (Cambridge, MA). The characteristics and sp. act. of the
purified rIL-12 preparation were previously described (20, 21). Murine rIFN- was obtained from Genzyme (Boston, MA). The
Ab used for ELISA assessment of IFN- were R4-6A2 and biotinylated
XMG1.2 mAb (both from BD PharMingen). Rabbit polyclonal IgG Ab specific
for IL-12R2 was raised in our laboratory as previously described
(9) and was used at a concentration of 10 µg/ml.
Neutralizing, affinity-purified sheep anti-mouse IL-12 p70
polyclonal Ab was provided by Genetics Institute and was used at 10
µg/ml.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Constructs were built in the pEF-BOS vector for the expression of
IL-23 and IL-12 fusion proteins (Fig. 1A). The cDNA were linked with
a 45-bp linker encoding the 15-aa
(Gly4Ser)3 linker (Fig. 1B). Constructs were compared for their ability to direct
bioactive protein expression in side-by-side screening experiments with
rIL-12 p70. Comparison of the results of the ELISA (Fig. 2A) specific for either the
p70 IL-12 heterodimer or the p40 subunit in the IL-12 fusion protein
suggested that the p40-specific ELISA quantitatively determines the
subunit in IL-12 and IL-23 fusion proteins. In contrast, the
p70-specific ELISA failed to detect IL-23. Comparable amounts of rIL-12
and fusion proteins were subjected to Western blot analysis under
reducing conditions using a p40-specific Ab (Fig. 2B). The
results showed that rIL-12 would run as a 45/50-kDa doublet, as
expected (22). In contrast, the fusion proteins were
expressed as single polypeptide chains of 115 and 120 kDa for IL-23 and
IL-12 fusion proteins, respectively. We thus analyzed the ability of
IL-23- and IL-12-Ig fusion proteins to induce IFN- production by Con
A blast T cells. On comparing a range of concentrations of either
rIL-12 or fusion proteins, we found that the IL-12 fusion protein
induced IFN- levels similar to those of the native cytokine, and
these levels were significantly higher than those induced by the
IL-23-Ig (Fig. 2C). Similar results have previously reported
for a human p19/p40 construct as compared with rIL-12
(2).
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Although most of the biological effects of IL-12 in vivo are
thought to involve direct actions on T and NK cells (6, 7), we have recently described autocrine effects of murine IL-12
on myeloid APC, including DC (8) and macrophages
(9). IL-12 was found to act on
CD8- DC (11) leading to the
activation of NF-B and the initiation of inflammatory and
Th1-promoting actions (8, 11). We therefore became
interested in analyzing the possible interaction of IL-23 on DC. We
used flow cytometry for detection of IL-23-Ig binding to freshly
harvested DC and a DC line. Using direct staining with fluoresceinated
IL-23-Ig or IL-12-Ig, we detected a high proportion of cells staining
positively for either fusion protein (Fig. 3). No significant difference was found
between freshly harvested DC and the DC line. In contrast, there was no
binding to either cell type by control fluoresceinated rIg.
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IL-12 actions on DC and macrophages include adjuvant effects that
confer priming ability on these cells pulsed with a synthetic peptide
(9, 11, 20, 21). In particular, DC and macrophages exposed
sequentially to rIL-12 and a tumor peptide, P815AB, will confer T
cell-mediated reactivity on prospective recipients of an intra-footpad
challenge with the peptide (18, 20, 21). We therefore
wanted to investigate whether similar adjuvant effects could be exerted
by IL-23 on peptide presentation by myeloid APC. Fig. 4 shows the effects of sensitization with
P815AB using freshly harvested DC exposed to IL-23-Ig or IL-12-Ig
before peptide pulsing and transfer into hosts to be assayed for skin
test reactivity at 2 wk. Similar to IL-12, IL-23 conferred priming
ability on DC pulsed with the peptide. In experiments not reported in
Fig. 4 we found that similar and comparable adjuvant activities were
exerted by IL-23- and IL-12-Ig on freshly harvested, highly purified
peritoneal macrophages (>99% Mac-1+)
(9). Therefore, both fusion proteins, under comparable
experimental conditions, would exert adjuvant activity on myeloid
APC.
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We have previously demonstrated that autocrine IL-12 may act
directly on DC to prime the cells for IL-12 production, with the
cytokine priming DC for NF-B-induced transcription of the IL-12 p40
gene (8). We therefore wanted to investigate any possible
autocrine effect of IL-23 on IL-12 production. We measured p70
production by ELISA in culture supernatants of freshly harvested DC
treated for 2 h with 10 ng/ml IL-23-Ig or IL-12-Ig (Fig. 5A). Additional groups were
treated with recombinant heterodimeric IL-12 or rIg. Culture
supernatants were harvested at 1 and 24 h. According to previous
results (8, 9), no p70 was found in any group at 1 h,
thus indicating that the p70 measured at later time points was not
derived from externally added IL-12. In contrast, considerable and
comparable amounts of the cytokine were found at 24 h in DC
exposed to recombinant (heterodimeric or single chain) IL-12 or to
IL-23-Ig. When a range of concentrations (0.1–100 ng/ml) of the two
fusion proteins were used, IL-23-Ig and IL-12-Ig were found to possess
comparable effects at 10–100 ng/ml (Fig. 5B). However, Fig. 5B also shows that the combined effects of IL-23-Ig and
IL-12-Ig would result in sustained IL-12 p70 production at 1–100 ng/ml
of each fusion protein.
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and TNF- and expression of phenotypic markers such as CD40,
CD80, and class II molecules. Under the experimental conditions
employed (i. e., 24- to 48-h exposure to a fusion protein), neither
IL-23-Ig nor IL-12-Ig significantly or reproducibly affected the
expression of CD40, CD80, or class II molecules (data not shown).
Similarly unaffected by either fusion protein appeared to be the
production of TNF- (data not shown). In contrast, both fusion
proteins induced considerable production of IFN- at 0.1–10 ng/ml
(Fig. 6). Again, the combined exposure of
DC to IL-12-Ig and IL-23-Ig appeared to result in additive effects on
cytokine production.
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The similarities between the activities of IL-23-Ig and IL-12-Ig
prompted us to investigate whether the two cytokines may be acting on
the same target cells. In fact, IL-12 is known to act selectively on
CD8- DC to enhance presentation of P815AB in
vivo (11). To this purpose splenic DC were fractionated to
yield a population of >99% CD8- cells and
>90% CD8+ cells (17). The two
subsets were analyzed by flow cytometry for the ability to bind
fluoresceinated IL-23-Ig in vitro (Fig. 7A) and to produce IL-12 p70
in response to IL-23-Ig (Fig. 7B). We found that IL-23 would
bind the two DC subsets equally well and that
CD8- and CD8+ DC subsets
would produce comparable amounts of IL-12 p70 in response to 10 ng/ml
IL-23-Ig. In addition, we wanted to examine CD8-
and CD8+ DC for the ability to prime the host in
vivo following sequential exposure to IL-12-Ig or IL-23-Ig and P815AB
(Fig. 8). In line with previous data
(11), we found that IL-12-Ig showed selective ability to
activate CD8- DC for presentation in vivo of the
peptide (Fig. 8A). In contrast, IL-23-Ig appeared to be able
to interact with both DC subsets to prime the host in vivo for skin
test reactivity to the tumor peptide (Fig. 8B).
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2 subunit Ab to block the activity of
IL-12, but not IL-23
The experiments reported above indicated that IL-23 may exert
biological effects on DC that are similar to but distinct from those of
IL-12, although a portion of IL-23 effects on DC could be mediated by
the induction of IL-12. In addition, it has been suggested that the
biological activity of naturally expressed IL-23 relies on interaction
with the IL-12R1 subunit and an additional, novel receptor subunit
(2). This would exclude a major role for the IL-12R2
subunit, which, in contrast, plays a major role in IL-12 signaling in T
cells (23). We have recently generated an IL-12R2
chain-specific Ab that detects this subunit in the IL-12R expressed by
different cell types (9). We took advantage of this
reagent to comparatively investigate the role of the 2 subunit in
the signaling of IL-23 and IL-12 in DC. According to the experimental
design illustrated above, the two fusion proteins were assayed for
adjuvant ability resulting from the activation in vitro of DC in the
presence or the absence of anti-2 Ab. The 2-specific Ab or
control rabbit Ig were present during the in vitro exposure of DC to
IL-23-Ig or IL-12-Ig before peptide pulsing and transfer into recipient
hosts to be assayed for skin test reactivity at 2 wk. Fig. 9 shows that the anti-2 Ab
completely blocked the effect of IL-12 on DC. In contrast, there was no
effect of the Ab added to cultures of DC exposed to IL-23-Ig. In line
with the lack of effect of anti-2 Ab on the activity of IL-23-Ig
was the observation that an Ab to IL-12 p70 present in the coculture in
place of the anti-2 reagent was equally devoid of any effect on
the expression of IL-23-Ig activity (Fig. 9). These findings confirm
the lack of a role for the IL-12R2 subunit in IL-23 signaling.
Furthermore, these data strongly suggest that most of the activity of
IL-23 on DC is not mediated by the induction of autocrine IL-12.
However, it should be noted that binding of the blocking Ab may not be
durable in vivo and/or that up-regulation of IL-12R2 may occur after
the adoptive transfer. Finally, it is also possible that, although not
strictly in an autocrine fashion, IL-23-stimulated DC may produce IL-12
in vivo that may act on other native DC.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 and IL-12R2 (23). p40, however,
may be involved in functional complexes with molecules other than p35
(28, 29), and in fact a novel p19 protein has recently
been described that engages p40 to form the newly described cytokine,
IL-23 (2, 3). The p19/p40 complex is naturally expressed
by activated human and murine DC and exerts activities on T cells that,
although similar to those of IL-12, can nevertheless be differentiated
from the latter.
In addition to direct actions on T cells, IL-12 may critically affect
the functions of accessory cells of the immune response, including DC
and macrophages (27). We have recently shown that rIL-12
acts selectively on CD8- DC (11)
and that autocrine production of IL-12 may be involved in DC modulation
via different immunotherapeutic maneuvers (10, 30). In
contrast, IL-6 will act on CD8+ DC to
down-modulate the tolerogenic properties of this subset of DC
(17) and may thus complement the adjuvant effect of IL-12
acting on CD8- DC. Therefore, a complex
interplay takes place among inflammatory cytokines that regulate the
functional activity of DC (31). Because it has been shown
that the biological activities of IL-23 on T cells result from
interaction of the p19/p40 complex with IL-12R1 (2), we
became interested in ascertaining any possible direct effect of IL-23
on murine splenic DC, the possible interplay and cross-regulation of
IL-12 and IL-23, and the possible sharing of receptor subunits with
particular regard to the 2 subunit. In fact, the 2 subunit
is a major component of the IL-12 signaling pathway in T cells
(23, 32).
By using single-chain IL-23-Ig or IL-12-Ig fusion proteins, we have
comparatively analyzed IL-23 and IL-12 for in vitro and in vivo effects
on DC. Analogous to their activities on T cells, we found that the two
cytokines may have similar as well as distinct effects on myeloid APC.
These would include increased production of endogenous IL-12 and
IFN- in vitro as well as induction in vivo of a combined
CD4+/CD8+ T cell response
to an otherwise poorly immunogenic tumor/self peptide
(18). However, in contrast to IL-12, which lacks direct
actions on CD8+ DC, the adjuvant effect in vivo
of IL-23 probably resulted from combined actions on
CD8- and CD8+ DC, and in
fact each subset alone, when treated with IL-23-Ig, was capable of
mediating the immunogenic presentation of the tumor peptide.
The adjuvant effect of IL-23 on the otherwise tolerogenic
CD8+ subset of murine DC is remarkably similar to
that of IL-6 (17), which we have previously shown to
mediate the effect of CD40 activation on these cells (30)
and to oppose the tolerogenic properties of IFN- (12).
CD8+ DC in the mouse may correspond in humans to
the progeny of DC precursors with a characteristic surface phenotype
and a plasmacytoid appearance (33) and may represent a
unique type of regulatory APC involved in tolerance and
immunosuppression (34). The finding that IL-23 may act
directly on those cells to promote the immunogenic presentation of an
otherwise tolerogenic tumor/self peptide (21) might
implicate a role of the cytokine not only in the generation of
protective immunity, but also in the promotion of autoimmunity,
according to a pattern similar to that of IL-12 (35).
Because most experimental studies aimed at assessing the role of IL-12
in autoimmunity have relied on the use neutralizing Ab that would block
the function of both p35/p40 and p19/p40, our present data may raise
further questions about the role of each individual cytokine in these
models of autoimmunity (2).
One major finding in this study was the ability of the IL-23-Ig fusion
protein to trigger the release of IL-12 from DC in vitro to an extent
comparable to that of rIL-12. This raised the issue of possible
bidirectional influences between the productions of IL-23 and IL-12. In
particular, we were concerned with the possibility that at least a
portion of the adjuvant effect of IL-23-Ig on DC could be mediated by
the endogenous production of IL-12. To investigate this issue, we took
advantage of the recent availability in our laboratory of neutralizing
Ab raised to the 2-chain of the IL-12R (9). We found
that the presence of this Ab as well as that of an anti-p70 reagent
during activation in vitro of DC with IL-23- or IL-12-Ig would
selectively block the adjuvant effect of the latter protein. Besides
emphasizing the critical role of 2 as a signal-transducing element
in IL-12 signaling, these data demonstrate that, similar to T cells
(2), 2 is not involved in the biological effects of
IL-23 on DC, and a significant portion of these effects is independent
of endogenous IL-12. On the other hand, in experiments not reported
here, we found that rIL-12 would increase the transcriptional
expression of murine p19 in DC, thus suggesting the occurrence of
mutual regulation between IL-12 and IL-23. As a corollary to the
current findings, our data suggest that the use of 2-specific Ab in
vivo may represent a suitable means of discriminating between the
relative roles of endogenous IL-12 and IL-23 in experimental models of
autoimmunity.
It has been suggested that IL-12 may represent a unique cytokine that
bridges innate resistance and Ag-specific adaptive immunity
(6). However, the critical 2 subunit required for IL-12
signaling is not present on freshly isolated native T cells and is
induced following TCR triggering (32). This condition is
different from that of DC, which constitutively express the 2-chain
(8). Although the putative receptor subunit involved in
IL-23 signaling in T cells has not been identified, there is evidence
that the latter chain, like IL-12R2, may not be expressed by naive T
cells and may be induced following TCR engagement. Our data suggest
that DC do express this subunit constitutively. This again underlines
the similarities between IL-12 and IL-23 and further suggests that the
latter cytokine may be involved early in the initiation of an
Ag-specific immune response. Interestingly in this regard we have found
that IL-23-Ig will induce IFN- production by DC to an extent similar
to IL-12 and that the combination of the two fusion proteins will
result in very high levels of IFN- production by DC. Because early
production of IFN- by APC is pivotal in determining the
effectiveness of an immune response to pathogens (27),
these data may underscore the potential role of IL-23 at the initiation
of immunity against microbial pathogens.
In conclusion, the recent discovery of p19/p40 as a novel composite factor closely related to IL-12 capable of critically affecting T cell functions raises important issues. We here show that, analogous to their effects on T cells, IL-12 and IL-23 may also exert similar as well distinct activities on DC, which play a central role in activating and regulating T cell responses. However, the activities of IL-23 may be even more complex than those of IL-12, encompassing effects on both CD8- and CD8+ DC. Given the crucial roles of these subsets in regulating the balance between immunogenic and tolerogenic stimuli in the early response to Ag, our data propose a critical role for IL-23 at the interface of innate and adaptive immunities.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Paolo Puccetti, Department of Experimental Medicine, Pharmacology Section, University of Perugia, Via del Giochetto, I-06126 Perugia, Italy. E-mail address: plopcc{at}tin.it
3 Abbreviations used in this paper: DC, dendritic cell; rIg, recombinant Ig protein.
Received for publication December 20, 2001. Accepted for publication March 19, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production and diminishes IL-4 inhibition of such priming. Proc. Natl. Acad. Sci. USA 90:10188.B and primes DC for IL-12 production. Immunity 9:315.[Medline]
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+ dendritic cells. Int. Immunol. 14:65.This article has been cited by other articles:
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  W. Liu, X. Ouyang, J. Yang, J. Liu, Q. Li, Y. Gu, M. Fukata, T. Lin, J. C. He, M. Abreu, et al. AP-1 Activated by Toll-like Receptors Regulates Expression of IL-23 p19 J. Biol. Chem., September 4, 2009; 284(36): 24006 - 24016. [Abstract] [Full Text] [PDF]
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S. Kohyama, S. Ohno, A. Isoda, O. Moriya, M. L. Belladonna, H. Hayashi, Y. Iwakura, T. Yoshimoto, T. Akatsuka, and M. Matsui IL-23 Enhances Host Defense against Vaccinia Virus Infection Via a Mechanism Partly Involving IL-17 J. Immunol., September 15, 2007; 179(6): 3917 - 3925. [Abstract] [Full Text] [PDF]
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N. Tokumasa, A. Suto, S.-i. Kagami, S. Furuta, K. Hirose, N. Watanabe, Y. Saito, K. Shimoda, I. Iwamoto, and H. Nakajima Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN-{gamma} production and the induction of Th1 cell differentiation Blood, July 15, 2007; 110(2): 553 - 560. [Abstract] [Full Text] [PDF]
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T. Kaiga, M. Sato, H. Kaneda, Y. Iwakura, T. Takayama, and H. Tahara Systemic Administration of IL-23 Induces Potent Antitumor Immunity Primarily Mediated through Th1-Type Response in Association with the Endogenously Expressed IL-12 J. Immunol., June 15, 2007; 178(12): 7571 - 7580. [Abstract] [Full Text] [PDF]
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R. J. Carmody, Q. Ruan, H.-C. Liou, and Y. H. Chen Essential Roles of c-Rel in TLR-Induced IL-23 p19 Gene Expression in Dendritic Cells J. Immunol., January 1, 2007; 178(1): 186 - 191. [Abstract] [Full Text] [PDF]
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H.-R. Kim, M.-L. Cho, K.-W. Kim, J.-Y. Juhn, S.-Y. Hwang, C.-H. Yoon, S.-H. Park, S.-H. Lee, and H.-Y. Kim Up-regulation of IL-23p19 expression in rheumatoid arthritis synovial fibroblasts by IL-17 through PI3-kinase-, NF-{kappa}B- and p38 MAPK-dependent signalling pathways Rheumatology, January 1, 2007; 46(1): 57 - 64. [Abstract] [Full Text] [PDF]
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T. M. Wozniak, A. A. Ryan, and W. J. Britton Interleukin-23 Restores Immunity to Mycobacterium tuberculosis Infection in IL-12p40-Deficient Mice and Is Not Required for the Development of IL-17-Secreting T Cell Responses J. Immunol., December 15, 2006; 177(12): 8684 - 8692. [Abstract] [Full Text] [PDF]
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 Y. S. Kim, S. H. Yang, H. G. Kang, E. Y. Seong, S. H. Lee, W. Gao, J. Kenny, X. X. Zheng, and T. B. Strom Distinctive role of donor strain immature dendritic cells in the creation of allograft tolerance Int. Immunol., December 1, 2006; 18(12): 1771 - 1777. [Abstract] [Full Text] [PDF]
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 M. C. Kullberg, D. Jankovic, C. G. Feng, S. Hue, P. L. Gorelick, B. S. McKenzie, D. J. Cua, F. Powrie, A. W. Cheever, K. J. Maloy, et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis J. Exp. Med., October 30, 2006; 203(11): 2485 - 2494. [Abstract] [Full Text] [PDF]
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M. Utsugi, K. Dobashi, T. Ishizuka, T. Kawata, T. Hisada, Y. Shimizu, A. Ono, and M. Mori Rac1 Negatively Regulates Lipopolysaccharide-Induced IL-23 p19 Expression in Human Macrophages and Dendritic Cells and NF-{kappa}B p65 trans Activation Plays a Novel Role J. Immunol., October 1, 2006; 177(7): 4550 - 4557. [Abstract] [Full Text] [PDF]
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 J. Hu, X. Yuan, M. L. Belladonna, J. M. Ong, S. Wachsmann-Hogiu, D. L. Farkas, K. L. Black, and J. S. Yu Induction of Potent Antitumor Immunity by Intratumoral Injection of Interleukin 23-Transduced Dendritic Cells. Cancer Res., September 1, 2006; 66(17): 8887 - 8896. [Abstract] [Full Text] [PDF]
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S. E. Moreno, J. C. Alves-Filho, T. M. Alfaya, J. S. da Silva, S. H. Ferreira, and F. Y. Liew IL-12, but Not IL-18, Is Critical to Neutrophil Activation and Resistance to Polymicrobial Sepsis Induced by Cecal Ligation and Puncture. J. Immunol., September 1, 2006; 177(5): 3218 - 3224. [Abstract] [Full Text] [PDF]
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A. N. Mathur, H.-C. Chang, D. G. Zisoulis, R. Kapur, M. L. Belladonna, G. S. Kansas, and M. H. Kaplan T-bet is a critical determinant in the instability of the IL-17-secreting T-helper phenotype Blood, September 1, 2006; 108(5): 1595 - 1601. [Abstract] [Full Text] [PDF]
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 S. Saito, M. Matsuura, and Y. Hirai Regulation of Lipopolysaccharide-Induced Interleukin-12 Production by Activation of Repressor Element GA-12 through Hyperactivation of the ERK Pathway. Clin. Vaccine Immunol., August 1, 2006; 13(8): 876 - 883. [Abstract] [Full Text] [PDF]
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Y. Li, N. Chu, A. Rostami, and G.-X. Zhang Dendritic Cells Transduced with SOCS-3 Exhibit a Tolerogenic/DC2 Phenotype That Directs Type 2 Th Cell Differentiation In Vitro and In Vivo J. Immunol., August 1, 2006; 177(3): 1679 - 1688. [Abstract] [Full Text] [PDF]
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S. A. Khader, S. Partida-Sanchez, G. Bell, D. M. Jelley-Gibbs, S. Swain, J. E. Pearl, N. Ghilardi, F. J. deSauvage, F. E. Lund, and A. M. Cooper Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection J. Exp. Med., July 10, 2006; 203(7): 1805 - 1815. [Abstract] [Full Text] [PDF]
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 A. Fernandez-Sesma, S. Marukian, B. J. Ebersole, D. Kaminski, M.-S. Park, T. Yuen, S. C. Sealfon, A. Garcia-Sastre, and T. M. Moran Influenza Virus Evades Innate and Adaptive Immunity via the NS1 Protein. J. Virol., July 1, 2006; 80(13): 6295 - 6304. [Abstract] [Full Text] [PDF]
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M. L. Belladonna, U. Grohmann, P. Guidetti, C. Volpi, R. Bianchi, M. C. Fioretti, R. Schwarcz, F. Fallarino, and P. Puccetti Kynurenine Pathway Enzymes in Dendritic Cells Initiate Tolerogenesis in the Absence of Functional IDO J. Immunol., July 1, 2006; 177(1): 130 - 137. [Abstract] [Full Text] [PDF]
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S. Oniki, H. Nagai, T. Horikawa, J. Furukawa, M. L. Belladonna, T. Yoshimoto, I. Hara, and C. Nishigori Interleukin-23 and interleukin-27 exert quite different antitumor and vaccine effects on poorly immunogenic melanoma. Cancer Res., June 15, 2006; 66(12): 6395 - 6404. [Abstract] [Full Text] [PDF]
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W. W. Overwijk, K. E. de Visser, F. H. Tirion, L. A. de Jong, T. W. H. Pols, Y. U. van der Velden, J. G. van den Boorn, A. M. Keller, W. A. Buurman, M. R. Theoret, et al. Immunological and Antitumor Effects of IL-23 as a Cancer Vaccine Adjuvant J. Immunol., May 1, 2006; 176(9): 5213 - 5222. [Abstract] [Full Text] [PDF]
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X. Yuan, J. Hu, M. L. Belladonna, K. L. Black, and J. S. Yu Interleukin-23-Expressing Bone Marrow-Derived Neural Stem-Like Cells Exhibit Antitumor Activity against Intracranial Glioma. Cancer Res., March 1, 2006; 66(5): 2630 - 2638. [Abstract] [Full Text] [PDF]
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G. Piskin, R. M. R. Sylva-Steenland, J. D. Bos, and M. B. M. Teunissen In Vitro and In Situ Expression of IL-23 by Keratinocytes in Healthy Skin and Psoriasis Lesions: Enhanced Expression in Psoriatic Skin J. Immunol., February 1, 2006; 176(3): 1908 - 1915. [Abstract] [Full Text] [PDF]
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M. A. Kleinschek, U. Muller, S. J. Brodie, W. Stenzel, G. Kohler, W. M. Blumenschein, R. K. Straubinger, T. McClanahan, R. A. Kastelein, and G. Alber IL-23 Enhances the Inflammatory Cell Response in Cryptococcus neoformans Infection and Induces a Cytokine Pattern Distinct from IL-12 J. Immunol., January 15, 2006; 176(2): 1098 - 1106. [Abstract] [Full Text] [PDF]
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 T. M. Wozniak, A. A. Ryan, J. A. Triccas, and W. J. Britton Plasmid Interleukin-23 (IL-23), but Not Plasmid IL-27, Enhances the Protective Efficacy of a DNA Vaccine against Mycobacterium tuberculosis Infection Infect. Immun., January 1, 2006; 74(1): 557 - 565. [Abstract] [Full Text] [PDF]
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S. Iwamoto, M. Ishida, K. Takahashi, K. Takeda, and A. Miyazaki Lipopolysaccharide stimulation converts vigorously washed dendritic cells (DCs) to nonexhausted DCs expressing CD70 and evoking long-lasting type 1 T cell responses J. Leukoc. Biol., August 1, 2005; 78(2): 383 - 392. [Abstract] [Full Text] [PDF]
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G. Fedele, P. Stefanelli, F. Spensieri, C. Fazio, P. Mastrantonio, and C. M. Ausiello Bordetella pertussis-Infected Human Monocyte-Derived Dendritic Cells Undergo Maturation and Induce Th1 Polarization and Interleukin-23 Expression Infect. Immun., March 1, 2005; 73(3): 1590 - 1597. [Abstract] [Full Text] [PDF]
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F. Fallarino, C. Asselin-Paturel, C. Vacca, R. Bianchi, S. Gizzi, M. C. Fioretti, G. Trinchieri, U. Grohmann, and P. Puccetti Murine Plasmacytoid Dendritic Cells Initiate the Immunosuppressive Pathway of Tryptophan Catabolism in Response to CD200 Receptor Engagement J. Immunol., September 15, 2004; 173(6): 3748 - 3754. [Abstract] [Full Text] [PDF]
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S. Kamiya, T. Owaki, N. Morishima, F. Fukai, J. Mizuguchi, and T. Yoshimoto An Indispensable Role for STAT1 in IL-27-Induced T-bet Expression but Not Proliferation of Naive CD4+ T Cells J. Immunol., September 15, 2004; 173(6): 3871 - 3877. [Abstract] [Full Text] [PDF]
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T. Yoshimoto, K. Okada, N. Morishima, S. Kamiya, T. Owaki, M. Asakawa, Y. Iwakura, F. Fukai, and J. Mizuguchi Induction of IgG2a Class Switching in B Cells by IL-27 J. Immunol., August 15, 2004; 173(4): 2479 - 2485. [Abstract] [Full Text] [PDF]
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L. A. Lieberman, F. Cardillo, A. M. Owyang, D. M. Rennick, D. J. Cua, R. A. Kastelein, and C. A. Hunter IL-23 Provides a Limited Mechanism of Resistance to Acute Toxoplasmosis in the Absence of IL-12 J. Immunol., August 1, 2004; 173(3): 1887 - 1893. [Abstract] [Full Text] [PDF]
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J. Liu, Z. Xiang, and X. Ma Role of IFN Regulatory Factor-1 and IL-12 in Immunological Resistance to Pathogenesis of N-Methyl-N-Nitrosourea-Induced T Lymphoma J. Immunol., July 15, 2004; 173(2): 1184 - 1193. [Abstract] [Full Text] [PDF]
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M. L. Salem, A. N. Kadima, Y. Zhou, C. L. Nguyen, M. P. Rubinstein, M. Demcheva, J. N. Vournakis, D. J. Cole, and W. E. Gillanders Paracrine Release of IL-12 Stimulates IFN-{gamma} Production and Dramatically Enhances the Antigen-Specific T Cell Response after Vaccination with a Novel Peptide-Based Cancer Vaccine J. Immunol., May 1, 2004; 172(9): 5159 - 5167. [Abstract] [Full Text] [PDF]
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 A. Hino, M.-N. Kweon, K. Fujihashi, J. R. McGhee, and H. Kiyono Pathological Role of Large Intestinal IL-12p40 for the Induction of Th2-Type Allergic Diarrhea Am. J. Pathol., April 1, 2004; 164(4): 1327 - 1335. [Abstract] [Full Text] [PDF]
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N. Ghilardi, N. Kljavin, Q. Chen, S. Lucas, A. L. Gurney, and F. J. de Sauvage Compromised Humoral and Delayed-Type Hypersensitivity Responses in IL-23-Deficient Mice J. Immunol., March 1, 2004; 172(5): 2827 - 2833. [Abstract] [Full Text] [PDF]
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S. H. Jackson, C.-R. Yu, R. M. Mahdi, S. Ebong, and C. E. Egwuagu Dendritic Cell Maturation Requires STAT1 and Is under Feedback Regulation by Suppressors of Cytokine Signaling J. Immunol., February 15, 2004; 172(4): 2307 - 2315. [Abstract] [Full Text] [PDF]
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M. Hisada, S. Kamiya, K. Fujita, M. L. Belladonna, T. Aoki, Y. Koyanagi, J. Mizuguchi, and T. Yoshimoto Potent Antitumor Activity of Interleukin-27 Cancer Res., February 1, 2004; 64(3): 1152 - 1156. [Abstract] [Full Text] [PDF]
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E. Lee, W. L. Trepicchio, J. L. Oestreicher, D. Pittman, F. Wang, F. Chamian, M. Dhodapkar, and J. G. Krueger Increased Expression of Interleukin 23 p19 and p40 in Lesional Skin of Patients with Psoriasis Vulgaris J. Exp. Med., January 5, 2004; 199(1): 125 - 130. [Abstract] [Full Text] [PDF]
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S.-J. Ha, D.-J. Kim, K.-H. Baek, Y.-D. Yun, and Y.-C. Sung IL-23 Induces Stronger Sustained CTL and Th1 Immune Responses Than IL-12 in Hepatitis C Virus Envelope Protein 2 DNA Immunization J. Immunol., January 1, 2004; 172(1): 525 - 531. [Abstract] [Full Text] [PDF]
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G.-X. Zhang, S. Yu, B. Gran, J. Li, I. Siglienti, X. Chen, D. Calida, E. Ventura, M. Kamoun, and A. Rostami Role of IL-12 Receptor {beta}1 in Regulation of T Cell Response by APC in Experimental Autoimmune Encephalomyelitis J. Immunol., November 1, 2003; 171(9): 4485 - 4492. [Abstract] [Full Text] [PDF]
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 T. Andrews and K. E. Sullivan Infections in Patients with Inherited Defects in Phagocytic Function Clin. Microbiol. Rev., October 1, 2003; 16(4): 597 - 621. [Abstract] [Full Text] [PDF]
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U. Grohmann, R. Bianchi, C. Orabona, F. Fallarino, C. Vacca, A. Micheletti, M. C. Fioretti, and P. Puccetti Functional Plasticity of Dendritic Cell Subsets as Mediated by CD40 Versus B7 Activation J. Immunol., September 1, 2003; 171(5): 2581 - 2587. [Abstract] [Full Text] [PDF]
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C.-H. Lo, S.-C. Lee, P.-Y. Wu, W.-Y. Pan, J. Su, C.-W. Cheng, S. R. Roffler, B.-L. Chiang, C.-N. Lee, C.-W. Wu, et al. Antitumor and Antimetastatic Activity of IL-23 J. Immunol., July 15, 2003; 171(2): 600 - 607. [Abstract] [Full Text] [PDF]
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T. Kopp, P. Lenz, C. Bello-Fernandez, R. A. Kastelein, T. S. Kupper, and G. Stingl IL-23 Production by Cosecretion of Endogenous p19 and Transgenic p40 in Keratin 14/p40 Transgenic Mice: Evidence for Enhanced Cutaneous Immunity J. Immunol., June 1, 2003; 170(11): 5438 - 5444. [Abstract] [Full Text] [PDF]
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C. S. R. Lankford and D. M. Frucht A unique role for IL-23 in promoting cellular immunity J. Leukoc. Biol., January 1, 2003; 73(1): 49 - 56. [Abstract] [Full Text] [PDF]
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