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*
Clinical Immunology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases; and
National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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exerts multiple biological activities in the modulation of
immune responses by the induction of transcription factors. One
transcriptional factor of the IFN regulatory factor family found to be
critical in regulating IL-12-dependent IFN- production in vivo
following infectious challenge has been designated IFN consensus
sequence-binding protein (ICSBP). In this study, the role of ICSBP in
regulating type 1 responses to T cell-specific stimulation in vitro was
assessed. Total splenocytes from ICSBP-/- mice stimulated
with soluble anti-CD3 were markedly impaired in the production of
IFN- compared with similarly stimulated cells from
ICSBP+/+ mice. Consistent with the decrease in IFN-
production, splenocytes from ICSBP-/- mice stimulated
with anti-CD3 in the presence or absence of IFN- or a soluble
CD40 ligand agonist failed to produce IL-12 p40 and IL-12 p70 protein;
however, the deficient production of IFN- from
ICSBP-/- mice could be restored by the addition of
anti-CD28 Ab in an IL-12-independent manner. In contrast to the
previous data, production of IFN- from naive
CD4+/LECAM-1high cells of
ICSBP-/- mice that had been primed in vitro with
anti-CD3 was similar to or greater than that of
ICSBP+/+ controls. In addition, the presence of IFN- in
priming cultures enhanced both priming for IFN- and IL-12
responsiveness from ICSBP-/- CD4+ T cells.
Overall, these results provide evidence that ICSBP is differentially
required for the ability of IFN- to regulate type 1 cytokine
responses from APCs and CD4+ T cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is the principal mechanism
linking innate and adaptive immunity to a variety of intracellular
infections (1). In this regard, IFN- has two important
roles. First, IFN- is the critical effector molecule leading to
activation of macrophages and subsequent intracellular killing. Second,
IFN-, by its ability to enhance IL-12 (2) and to
inhibit IL-10 production (3), leads to the maintenance of
a Th1-type response. Due to the diverse and important functions of
IFN-, there has been great interest in studying the transcription
factors that control IFN- activity.
The ability of IFN (type I and type II) to regulate transcription is
controlled in large part by a group of proteins such as IRF-1, IRF-2,
and IFN consensus sequence-binding protein
(ICSBP),2 which belong to the IFN
regulatory factor (IRF) family of transcription factors
(4, 5, 6, 7, 8). These proteins function by binding to the
IFN-stimulated response element found in promoters of IFN-inducible
genes. ICSBP is unique among these factors in that it is expressed
exclusively in cells of the immune system (9) such as
activated T cells (10) and macrophages (11, 12). In addition, ICSBP is notable for its regulation by IFN-
as well as of IFN-
ß.
Recently, several studies have used ICSBP-/- mice to
examine its role in regulating the immune response to a variety of
infectious pathogens (13, 14, 15, 16). In murine models of
Listeria monocytogenes (14), Leishmania
major (15), and Toxoplasma gondii
(16), the fact that ICSBP-/- mice had
enhanced susceptibility provided clear evidence for its importance for
infections requiring IL-12-dependent production of IFN-. In these
studies, it was directly shown that IL-12 production was markedly
reduced (15, 16). Moreover, IL-12 production could not be
restored from cells of ICSBP-/- mice in response to
microbial stimuli even in the presence of exogenous IFN- (15, 16). These results provided clear evidence for the importance of
ICSBP in IL-12 induction in response to intracellular pathogens as well
as for the ability of IFN- to enhance IL-12 transcription
(2). The role of ICSBP in regulating IFN- production in
response to T cell stimuli has also been studied. Initial work showed
that IFN- production was reduced from total spleen cells of
ICSBP-/- mice compared with that of the controls
(13) following stimulation with Con A; however, these data
contrasted with a recent report showing that IFN- production was
similar for cells of ICSBP-/- and ICSBP+/+
mice in response to Con A (16). In addition, a recent
study showed that purified CD4+ T cells from
ICSBP-/- mice stimulated in vitro with a polyclonal T
cell mitogen and exogenous IL-12 still had decreased production of
IFN-. Thus, based on the aforementioned data, the role of ICSBP in
regulating type 1 immune responses following T cell stimulation is
still not entirely clear. Furthermore, while the ability of IFN- to
induce IL-12 from APCs is ICSBP dependent, whether ICSBP is also
required for IFN- to regulate T cell differentiation has not been
examined.
In the studies reported here, we first established the role of ICSBP in
regulating type 1 cytokine responses from spleen cells in response to
anti-CD3 stimulation. In addition, since IFN- can influence
CD4+ T cell differentiation (17) and IL-12
responsiveness (18), we determined whether ICSBP was
required for the effects of IFN- on these functions. Our results are
consistent with previous reports showing that ICSBP is required for
IL-12 production in response to a T cell stimulus. In addition, they
confirm that IFN- requires ICSBP to enhance IL-12 production from
APCs. By contrast, the presence of IFN- in priming cultures resulted
in enhanced priming for IFN- and IL-12 responsiveness from naive
CD4+ T cells of ICSBP-/- mice. Overall, these
data suggest that the requirement of ICSBP for type 1 cytokine
responses is cell specific, restricted to IL-12 induction by APCs in
response to microbial or T cell stimuli. Moreover, ICSBP does not
appear to be required for IFN- to influence CD4+ T cell
differentiation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female ICSBP wild-type (ICSBP+/+) and ICSBP-deficient (ICSBP-/-) mice were generated as previously described (13) and used at the seventh generation of back-crossing to the C57BL/6 strain. Animals were kept under pathogen-free conditions. Mice used were between 6 and 8 wk of age.
Media and reagents
HBSS (Biofluids, Rockville, MD) was used as wash medium. Complete culture medium consisted of RPMI 1640 supplemented with 10% heat-inactivated FCS, penicillin (100 U/ml), streptomycin (100 µg/ml), sodium pyruvate (1 mM), L-glutamine (2 mM), and 2-ME (50 µM), all of which were purchased from Biofluids. Staphylococcus aureus Cowan strain (SAC) was purchased from Sigma (St. Louis, MO).
Recombinant cytokines and Abs
rIL-2 was purchased from Genzyme (Cambridge, MA). Mouse rIL-4
and purified monoclonal rat antimouse IL-4 (11B11) were prepared as
previously described (19). One unit of IL-4 is equivalent
to 
0.5 pg. Mouse rIFN-, purified rat anti-mouse IFN-,
purified rat anti-mouse IL-10, anti-CD4, and
anti-lymphocyte endothelial cell adhesion molecule-1
(anti-LECAM-1) were purchased from PharMingen (San Diego, CA).
Anti-CD3 (2C11) was a generous gift of Dr. Jeffrey Bluestone
(University of Chicago, Chicago, IL). Anti-CD28 ascites was a generous
gift of Dr. James Allison (University of California, Berkeley, CA).
Mouse rIL-12 and Abs to mouse IL-12 were generous gifts of Dr. Maurice
Gately (Hoffman-La Roche, Nutley, NJ). A soluble CD40 ligand (CD40L)
agonist (CD40 ligand/trimer (CD40LT)) was a generous gift of Immunex
(Seattle, WA).
Preparation of splenocytes and culture condition
Total splenocytes were prepared from pooled spleens on Ficoll gradient (Sigma). Cells were cultured in 96-well plates at 4 x 105 cells/well in a total volume of 200 µl in complete culture medium. Cultures were incubated in the presence or absence of stimuli as indicated in the figure legends. The supernatants from these cells were used to measure the induction of cytokines by ELISA.
Preparation of CD4+ T cells
Lymph node CD4+ T cells from ICSBP+/+ and -/- mice were prepared in the following manner. Pooled lymph node cells were removed from ICSBP+/+ and ICSBP-/- mice and passed over a CD4 subset column (R&D Systems, Minneapolis, MN). Cells were then stained with phycoerythrin-labeled anti-CD4 and FITC-labeled LECAM-1 (Mel 14). These cells were subjected to FACS with a FACStarPlus (Becton Dickinson, Sunnyvale, CA). Post-sort analysis revealed >99% CD4+/LECAM-1high T cells.
Primary and secondary stimulation of CD4+ T cells
Sorted CD4+/LECAM-1high cells were plated at a density of 5–7 x 105 cells/well in a total volume of 1.5 ml in 24-well plates precoated with anti-CD3 Ab at 5 µg/ml in coating buffer (borate-buffered saline; pH 8.5). Cytokines and Abs were added to wells at the initiation of cultures as indicated in the figure legends. After 4 days, cells were harvested and washed three times, and 1–2 x 105 cells were restimulated with immobilized anti-CD3 plus soluble anti-CD28 Abs in a total volume of 200 µl/well in 96-well plates. Forty-eight hours later, supernatants were collected and assayed for lymphokine.
Measurement of cytokine production
Measurement of IFN- and IL-4 were assessed by specific ELISA
as previously described (19). The lower limit of detection
of IFN- and IL-4 was 30 pg/ml and 2 pg/ml, respectively. IL-12 p70
ELISA was performed with a kit from Genzyme with a sensitivity of 10
pg/ml. Mouse IL-12 p40 ELISA was performed as described
(16). The lower limit of p40 was 20 pg/ml. In all
experiments, serial dilutions of supernatants were used to measure
cytokine content in each separate ELISA. Supernatants were assayed in
triplicate for all experiments.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production from splenocytes of
ICSBP-/- mice is independent of
IL-4 and IL-10
Previous studies have shown that ICSBP is required for IL-12
production in response to various microbial stimuli (15, 16). In contrast, the role of ICSBP in regulating IL-12
production in response to T cell stimuli is less well defined. In this
regard, several reports have shown that production of IFN- from
spleen cells of ICSBP-/- and ICSBP+/+ mice in
response to Con A was similar (16). As IFN- is often a
sensitive bioassay for IL-12 activity, these data raise several
possibilities. First is that there is an
ICSBP-independent/IL-12-independent pathway for IFN- production in
response to a T cell mitogen. Alternatively, since IL-12-dependent
production of IFN- in response to T cell stimulation is CD40L/CD40
dependent (20, 21), the possibility exists that this
costimulatory pathway is mediating IL-12-dependent/ICSBP-independent
induction of IFN- in response to Con A. Finally, it has been
previously reported that mRNA expression for IL-4 and IL-10, cytokines
known to inhibit IFN- production, is increased in
ICSBP-/- mice (15, 16). The following series
of experiments was initiated to assess these possibilities.
As shown in Fig. 1
, production of IFN-
was markedly inhibited from spleen cells of ICSBP-/- mice
compared with cells from the control ICSBP+/+ mice in
response to anti-CD3 alone. Addition of neutralizing Abs to IL-4
and/or IL-10 to cultures did not restore the production of IFN- from
cells of ICSBP-/- mice. In contrast, addition of
anti-IL-12 to cultures strikingly inhibited IFN- produced from
cells of control ICSBP+/+ mice. Taken together, these data
suggest the decrease in IFN- from ICSBP-/- mice in
response to a T cell stimulus is likely due to deficient IL-12
production and not to the inhibitory effects of IL-4 or IL-10.
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production from cells of
ICSBP-/- mice in response to
anti-CD3
In the previous figure, while IFN- was substantially diminished
from cells of ICSBP-/- mice or ICSBP+/+ mice
stimulated in the presence of anti-IL-12, there was still an
appreciable amount induced in response to anti-CD3. As IFN-
produced in response to T cell stimuli is controlled in large part by
CD40L/CD40 induction of IL-12 and/or CD28/B7 stimulation
(21), the role of these costimulatory interactions in
regulating IFN- production was assessed. As shown in Fig. 2, consistent with the results seen
above, IFN- produced from ICSBP-/- mice stimulated
with anti-CD3 was significantly less than that from
ICSBP+/+ mice and was not affected by addition of
anti-IL-12 to the cultures; however, addition of anti-CD40L Ab
completely inhibited the production of IFN-. Furthermore, addition
of a stimulatory anti-CD28 mAb to the cultures strikingly enhanced
production of IFN- from cells of ICSBP-/- mice similar
to that induced from the ICSBP+/+ mice. The CD28-mediated
enhancement of IFN- was not inhibited by the presence of
anti-IL-12 or anti-CD40L mAb in the cultures. These data are
consistent with the ability of CD40L/CD40 costimulation to enhance
IFN- production through a CD28-dependent/IL-12-independent mechanism
and provide strong evidence that the capacity of total spleen cells
from ICSBP-/- mice to produce IFN- in response to a T
cell mitogen and exogenous CD28 stimulation is relatively normal.
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response from cells of ICSBP-/- mice was further
evaluated. First, unstimulated total splenocytes from
ICSBP+/+ and ICSBP-/- mice had similar
expression of B7.1 and B7.2 (data not shown). Of interest, while
expression of B7-1 was also similar from both groups of mice following
stimulation with anti-CD3, B7.2 expression was increased 2-fold on
ICSBP+/+ cells. Finally, the proliferative response of
ICSBP+/+ cells in response to anti-CD3 was also
increased compared with that of ICSBP-/- cells. Overall,
these data suggest that in response to anti-CD3, there is less
activation of the cells from the ICSBP-/- mice.
ICSBP is differentially required for the regulatory
effects of IFN- and IL-10 on
IL-12 p40 production
To directly show that ICSBP is required for IL-12 production
in response to anti-CD3, IL-12 p40 and p70 production was assessed
following stimulation with various mitogens. As shown in Tables
I and II,
cells from ICSBP-/- mice stimulated with anti-CD3 in
the presence or absence of anti-CD28 produced no detectable IL-12
p40 or p70, consistent with the results shown above. In addition, there
was no detectable IL-12 p70 from ICSBP-/- mice stimulated
with a potent inducer of IL-12 such as SAC (Table I). Furthermore,
while the addition of IFN- caused an increase in IL-12 p40 (Tables I
and II) and IL-12 p70 (Table I) from cells of wild-type mice stimulated
with SAC or LPS, addition of IFN- did not enhance IL-12 p40 or p70
from cells of ICSBP-/- mice. While these results are
consistent with previous data showing that ICSBP is required for the
ability of IFN- to enhance IL-12 (2), we were also
interested in how ICSBP may effect negative regulators of IL-12
production. In this regard, the addition of anti-IL-10 mAb to
cultures caused a striking enhancement in IL-12 p40 from cells of both
ICSBP-/- and ICSBP+/+ mice in response to
SAC. Taken together, these results suggest that IL-12 p40 transcription
may be differentially regulated, in that ICSBP does not affect
IL-10-mediated inhibition of IL-12 expression while it critically
affects IFN--mediated induction of IL-12.
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enhancement of Th1 priming is
independent of ICSBP and IL-12
Since ICSBP is essential for IFN- to enhance IL-12
production from macrophages (15, 16) and IFN- has been
shown to be a potent regulator of Th1 differentiation
(17), it was of interest to study whether ICSBP was also
required for IFN- to influence CD4+ T cell
differentiation. To this end, highly purified naive CD4+ T
cells from ICSBP-/- and ICSBP+/+ mice were
primed in vitro under a variety of conditions, and IFN- production
was determined following in vitro restimulation. As shown in Fig. 3, sorted
CD4+/LECAM-1high cells from
ICSBP-/- stimulated with immobilized anti-CD3 plus
soluble CD28 for 4 days and restimulated produced amounts of IFN-
comparable with that of the control mice. Addition of IFN- to
priming cultures caused a three- to fourfold increase in IFN-
production following restimulation from cells of both
ICSBP-/- and ICSBP+/+ mice. Of note, the
presence of IFN- in priming cultures also caused a decrease in IL-4
production (Fig. 3B). Moreover, the fact that addition of
anti-IFN- to priming cultures caused a decrease in production of
IFN- further supports a role for endogenous IFN- in regulating
Th1 differentiation. Thus, these data clearly show that naive
CD4+ T cells from ICSBP-/- mice are not
deficient in their production of IFN- when stimulated in an
IL-12-independent system. Moreover, it should be noted that in a
separate experiment, sorted CD4+ T cells from
ICSBP-/- mice stimulated with immobilized anti-CD3 in
the absence of CD28 stimulation produced comparable amounts of IFN-
to similarly stimulated wild-type mice. This suggests that ICSBP is
not required for production of IFN- from naive cells even under
these more limiting (absence of CD28) stimulatory conditions. Finally,
the fact that IFN- is able to influence Th1 differentiation in the
absence of ICSBP provides strong evidence that the major biologic
effects of ICSBP on type 1 immune responses are relatively cell
specific.
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augments IL-12 responsiveness
in ICSBP-/- mice
Another important mechanism by which IFN- affects T cell
priming is through its ability to enhance IL-12 responsiveness by
increasing IL-12 Rß2 expression (18). To evaluate the
role of endogenous IFN- on IL-12 responsiveness, sorted
CD4+/LECAM-1high T cells from
ICSBP-/- mice were stimulated in primary cultures with
anti-CD3 in the presence or absence of anti-IFN- or IL-4.
After 4 days, cells were restimulated with or without IL-12, and
production of IFN- was determined. As shown in Fig.
4A, addition of IL-12 to the
secondary cultures caused a three- to fourfold increase in production
of IFN- from cells primed with anti-CD3 alone; however, addition
of anti-IFN- or IL-4 in primary cultures strongly inhibited the
ability of IL-12 to enhance production of IFN- in secondary
cultures. By contrast, addition of IFN- or IL-12 to primary cultures
caused a striking increase in IFN- production in the presence or
absence of IL-12 in secondary cultures (Fig. 4B). Taken
together, these data underscore that the ability of IFN- to regulate
T cell differentiation in CD4+ T cells is maintained in
ICSBP-/- mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-independent
manner, T cell stimuli require CD40L/CD40 stimulation. Recently, a
better understanding of the molecular basis for IL-12 regulation has
come from studies using ICSBP-/- mice. These studies
convincingly showed that induction of IL-12 in response to a variety of
microbial stimuli is markedly impaired in ICSBP-/- mice,
resulting in substantially diminished production of IFN- (15, 16). It should be noted, however, that in some of the previous
reports, production of IFN- from spleen cells of
ICSBP-/- mice is only modestly affected, suggesting that
induction of IL-12 by T cell stimuli may be intact and not require
ICSBP. Alternatively, as CD40L/CD40 stimulation induced by Con A can
also enhance expression of B7/CD28, it is possible that production of
IFN- was independent of IL-12. In the studies reported here, we show
directly that IL-12 p40 production from spleen cells of
ICSBP-/- mice in response to anti-CD3 is markedly
inhibited. Moreover, addition of a CD40 ligand agonist to cultures
still did not enhance IL-12 production. Since levels of ICSBP
expression in unstimulated APCs are low, our results raise the
possibility that CD40L/CD40 stimulates induction of ICSBP in these
cells, similar to that by IFN- stimulation (11).
Finally, our results showing that addition of a stimulatory
anti-CD28 Ab strikingly enhanced production of IFN- from spleen
cells of ICSBP-/- mice in response to anti-CD3, even
in the presence of anti-IL-12, suggest that IL-12-independent
production of IFN- is mediated by CD40L/CD40 enhancement of B7. We
conclude that ICSBP is essential for IL-12 p70 induction and for
IL-12-dependent production of IFN- in response to both microbial and
T cell stimuli.
A second major focus of this study was to determine whether ICSBP was
essential for the ability of IFN- to regulate type 1 cytokine
responses. Previous studies have shown that upstream events such as
STAT 1 activation and production of nitric oxide are intact in
ICSBP-/- mice (16), suggesting that the
effects of ICSBP act downstream of the STAT 1 pathway and affect a more
limited number of IFN--inducible genes. In this regard, our results
are consistent with recent reports showing that ICSBP is required for
the ability of IFN- to enhance IL-12 p40 production (15, 16). Of additional interest was the finding that spleen cells
from ICSBP-/- mice stimulated with SAC and anti-IL-10
had a demonstrable increase in IL-12 p40 but not in p70. Thus, ICSBP is
not likely to regulate IL-10-mediated inhibition of IL-12 production.
Finally, there is evidence showing that IFN- can directly influence
the differentiation of naive CD4+ T cells toward a Th1-type
cell (17). Moreover, IFN- has also been shown to
enhance Th1 differentiation by enhancing the expression of the IL-12
Rß2 chain on CD4+ T cells (18). In these
studies, we first show that, in an IL-12-independent system, the
absence of ICSBP does not affect Th1 differentiation. In addition, the
presence of IFN- in priming cultures both enhanced the priming for
IFN- itself and increased IL-12 responsiveness. Overall, these
results show that the role of ICSBP in regulating type 1 cytokine
responses is cell specific and is limited to its effects on IL-12 p40
production but is not required for IFN- to influence
CD4+ T cell differentiation. This latter observation may
have biologic and clinical relevance in the following manner. It was
recently reported that a small number of individuals with a mutation in
the IL-12R ß1 chain have increased susceptibility to intracellular
pathogens such as Mycobacterium avium, BCG, or
Salmonella enteritidis infection (22, 23). In
these studies, it was of interest that these patients still produced
appreciable amounts of IFN- (>1 ng/ml) in response to mitogenic
stimulation. Furthermore, it was noted that IL-12Rß1-/-
patients had a milder clinical course than did similarly infected
patients with IFN-R deficiency (24, 25). Based on these
observations, the authors concluded that this milder clinical course
might be due to the existence of IL-12-independent pathways for IFN-
production. Moreover, it was speculated that this IL-12-independent
production of IFN- may have had an immunological effect, insofar as
they were not able to detect IL-4. These data further underscore the
fact that for most intracellular infections, while IL-12 affects the
magnitude of the Th1 response, IFN- is the critical effector
cytokine in mediating intracellular killing. Furthermore, the findings
reported here that IFN- can still affect the differentiation of Th1
and Th2 responses by CD4+ T cells in the absence of ICSBP
leaves open the possibility that in settings in which IL-12 or IL-12
responsiveness is markedly diminished, the relatively small amount of
IFN- produced may still exert a biologic and immunologic effect as
demonstrated in these patients.
To conclude, we speculate that the differential requirement for ICSBP in regulating type 1 cytokine production observed in APCs and naive T cells may be attributable to distinct contributions of other IRF family proteins such as Pip/IRF4 in these respective cell types. In this regard, Pip/IRF-4 is highly homologous to ICSBP in structure and is induced by similar stimuli in lymphoid cells (26, 27). Work is under way to determine whether compensatory mechanisms exist in T cells to obviate the need for ICSBP in controlling Th1 differentiation.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: ICSBP, IFN consensus sequence binding protein; SAC, Staphylococcus aureus Cowan strain 1; CD40L, CD40 ligand; IRF, IFN regulatory factor; LECAM-1, lymphocyte endothelial cell adhesion molecule-1; CD40LT, CD40 ligand/trimer
Received for publication July 23, 1998. Accepted for publication October 7, 1998.
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in monocytic cells. J. Exp. Med. 183:147. inhibits IL-10 production by monocytes. J. Exp. Med. 177:523.-regulated protein that binds the IFN-inducible enhancer element of major histocompatibility complex class I genes. Proc. Natl. Acad. Sci. USA 87:3743.-IFN-responsive transcription factor is related to IFN regulatory factor and Myb families of DNA binding proteins. Mol. Cell. Biol. 12:3315.-induced nuclear expression of IFN consensus sequence binding protein in murine peritoneal macrophages. J. Immunol. 152:2270.[Abstract]
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  M. Milanovic, G. Terszowski, D. Struck, O. Liesenfeld, and D. Carstanjen IFN Consensus Sequence Binding Protein (Icsbp) Is Critical for Eosinophil Development J. Immunol., October 1, 2008; 181(7): 5045 - 5053. [Abstract] [Full Text] [PDF]
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 A. Burchert, D. Cai, L. C. Hofbauer, M. K. R. Samuelsson, E. P. Slater, J. Duyster, M. Ritter, A. Hochhaus, R. Muller, M. Eilers, et al. Interferon consensus sequence binding protein (ICSBP; IRF-8) antagonizes BCR/ABL and down-regulates bcl-2 Blood, May 1, 2004; 103(9): 3480 - 3489. [Abstract] [Full Text] [PDF]
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G. Schiavoni, F. Mattei, P. Borghi, P. Sestili, M. Venditti, H. C. Morse III, F. Belardelli, and L. Gabriele ICSBP is critically involved in the normal development and trafficking of Langerhans cells and dermal dendritic cells Blood, March 15, 2004; 103(6): 2221 - 2228. [Abstract] [Full Text] [PDF]
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 C. Zhu, K. Rao, H. Xiong, K. Gagnidze, F. Li, C. Horvath, and S. Plevy Activation of the Murine Interleukin-12 p40 Promoter by Functional Interactions between NFAT and ICSBP J. Biol. Chem., October 10, 2003; 278(41): 39372 - 39382. [Abstract] [Full Text] [PDF]
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 C. Buono, C. E. Come, G. Stavrakis, G. F. Maguire, P. W. Connelly, and A. H. Lichtman Influence of Interferon-{gamma} on the Extent and Phenotype of Diet-Induced Atherosclerosis in the LDLR-Deficient Mouse Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 454 - 460. [Abstract] [Full Text] [PDF]
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H. Xiong, C. Zhu, H. Li, F. Chen, L. Mayer, K. Ozato, J. C. Unkeless, and S. E. Plevy Complex Formation of the Interferon (IFN) Consensus Sequence-binding Protein with IRF-1 Is Essential for Murine Macrophage IFN-gamma -induced iNOS Gene Expression J. Biol. Chem., January 17, 2003; 278(4): 2271 - 2277. [Abstract] [Full Text] [PDF]
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J. Aliberti, O. Schulz, D. J. Pennington, H. Tsujimura, C. R. e Sousa, K. Ozato, and A. Sher Essential role for ICSBP in the in vivo development of murine CD8alpha + dendritic cells Blood, January 1, 2003; 101(1): 305 - 310. [Abstract] [Full Text] [PDF]
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 G. Schiavoni, F. Mattei, P. Sestili, P. Borghi, M. Venditti, H. C. Morse III, F. Belardelli, and L. Gabriele ICSBP Is Essential for the Development of Mouse Type I Interferon-producing Cells and for the Generation and Activation of CD8{alpha}+ Dendritic Cells J. Exp. Med., December 2, 2002; 196(11): 1415 - 1425. [Abstract] [Full Text] [PDF]
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H. Tsujimura, T. Nagamura-Inoue, T. Tamura, and K. Ozato IFN Consensus Sequence Binding Protein/IFN Regulatory Factor-8 Guides Bone Marrow Progenitor Cells Toward the Macrophage Lineage J. Immunol., August 1, 2002; 169(3): 1261 - 1269. [Abstract] [Full Text] [PDF]
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I-M. Wang, C. Contursi, A. Masumi, X. Ma, G. Trinchieri, and K. Ozato An IFN-{gamma}-Inducible Transcription Factor, IFN Consensus Sequence Binding Protein (ICSBP), Stimulates IL-12 p40 Expression in Macrophages J. Immunol., July 1, 2000; 165(1): 271 - 279. [Abstract] [Full Text] [PDF]
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 J. Hein, V. A. J. Kempf, J. Diebold, N. Bucheler, S. Preger, I. Horak, A. Sing, U. Kramer, and I. B. Autenrieth Interferon Consensus Sequence Binding Protein Confers Resistance against Yersinia enterocolitica Infect. Immun., March 1, 2000; 68(3): 1408 - 1417. [Abstract] [Full Text] [PDF]
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 S. X. Hao and R. Ren Expression of Interferon Consensus Sequence Binding Protein (ICSBP) Is Downregulated in Bcr-Abl-Induced Murine Chronic Myelogenous Leukemia-Like Disease, and Forced Coexpression of ICSBP Inhibits Bcr-Abl-Induced Myeloproliferative Disorder Mol. Cell. Biol., February 15, 2000; 20(4): 1149 - 1161. [Abstract] [Full Text]
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 C. Contursi, I-M. Wang, L. Gabriele, M. Gadina, J. O'Shea, H. C. Morse III, and K. Ozato IFN consensus sequence binding protein potentiates STAT1-dependent activation of IFNgamma -responsive promoters in macrophages PNAS, January 4, 2000; 97(1): 91 - 96. [Abstract] [Full Text] [PDF]
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Y.-M. Kim, H.-S. Kang, S.-G. Paik, K.-H. Pyun, K. L. Anderson, B. E. Torbett, and I. Choi Roles of IFN Consensus Sequence Binding Protein and PU.1 in Regulating IL-18 Gene Expression J. Immunol., August 15, 1999; 163(4): 2000 - 2007. [Abstract] [Full Text] [PDF]
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