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*
Immune Cell Signal Transduction RU, Korea Research Institute of Bioscience and Biotechnology, Taejon, Republic of Korea;
Department of Biology, Chungnam National University, Taejon, Republic of Korea; and
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-18 increases IFN-
production from Th1 cells, induces NK cell
cytotoxicity, and activates Th1 cell proliferation. IL-18 shares some
of its biological activities with IL-12. IL-18 induces the fungicidal
activity of murine peritoneal exudate cells against Cryptococcus
neoformans through IFN- production in the presence of IL-12
(6), and it also inhibits IgE production by induction of
IFN- production from the activated B cells in the presence of IL-12
(7). Recently, the IL-18R was purified from the Hodgkin’s
disease cell line, L428, and identified as IL-1Rrp (8).
IL-18 activates NF-
B, p56lck, and
mitogen-activated protein kinase in Th1 cells (9, 10). In
addition, it shows a variety of in vitro biological activities, such as
potentiating T cell development in the presence of IL-12
(11) and initiating production of proinflammatory
cytokines (12). In vivo studies also demonstrated that it
has diverse effects on liver inflammation and injury (13),
cytotoxicity (14, 15), and tumor regression
(16).
Like other cytokines, IL-18 is expressed from many different types of cells and tissues, including Kupffer cells, P. acnes-induced peritoneal cells (1), epidermal keratinocytes (17), osteoblastic cells (18), brain (19), and adrenal cortex (20). However, little is known about the physiological stimuli that induce IL-18 gene expression. Recently, Tone et al. (21) reported that IL-18 gene expression is controlled by the activities of two promoters, which have no TATA and G+C-rich region. It was also demonstrated that an upstream promoter is inducible by LPS or PMA plus ionomycin, and a downstream promoter has constitutive activity.
To understand the regulatory elements in both promoters, we assayed the promoter activities of deleted and site-directed mutated promoter constructs. It was found that PU.1 is a critical site for maximal activity of the downstream promoter, and ICSBP is critical for the activity of the upstream promoter. Possible interactions between the two promoters are also discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Bacterial LPS (from Escherichia coli serotype 0127:
B8) and TLC plates (silica gel) were purchased from Sigma (St. Louis,
MO). Poly(dI-dC)·poly(dI-dC) and dNTPs were obtained from Pharmacia
LKB Biotechnology (Piscataway, NJ).
1-Deoxydichloroacetyl-1-[14C]chloramphenicol
and [
-32P]dCTP were purchased from Amersham
(Aylesbury, U.K.). Restriction enzymes, Klenow fragment of DNA pol. I,
BSA, and acetyl-CoA were purchased from Boehringer Mannheim (Mannheim,
Germany). The ICSBP cDNA construct was provided by Dr. Ben-Zion Levi
(Technion-Israel Institute of Technology, Haifa, Israel). The
polyclonal Abs against IRF-1, PU.1, or ICSBP were purchased from Santa
Cruz Biotechnology (Santa Cruz, CA).
Cell isolation and culture
The mouse macrophage-like cell line RAW 264.7 was obtained from American Type Culture Collection (Manassas, VA). Cells were cultured in DMEM supplemented with 2 mM L-glutamine, antibiotics (100 U/ml penicillin G and 100 µg/ml streptomycin), and 10% heat-inactivated FBS (Life Technologies/BRL, Gaithersburg, MD; complete medium) and were maintained at 37°C in a humidified incubator containing 5% CO2. Isolation of starting populations of hemopoietic cells from normal or PU.1 null liver were obtained from 1-day-old neonates. The generation of myeloid cells and neutrophils from normal and PU.1 null myeloid cells has been described (22, 23). Macrophages were obtained from the identical source and were separated by virtue of adherence and subsequent growth in 5000 U/ml of recombinant mouse M-CSF. The generation and characterization of the PU.1-deficient myeloid cell line, 503, as well as the generation of sublines of the 503 line restored with PU.1 or M-CSF receptor have been described previously (23). Primary PU.1 null myeloid cells were restored with PU.1 using retroviral transduction. Briefly, the wells of a 24-well tissue culture plate (Costar, Cambridge, MA) were incubated with a 10 µg/ml solution of fibronectin (Sigma) at 37oC for 2 h. Fibronectin was aspirated, wells were washed, and 0.5 x 106 CFU/ml of the amphotropic retroviral vector containing the complete coding region of PU.1 was added. The plate was further incubated for 1 h at 37oC to allow adherence of viral particles to the fibronectin-coated surface. Hemopoietic cells (0.5 x 106) were then added in a minimal volume of medium plus Polybrene (final concentration, 6–8 µg/ml), and the plate was centrifuged at 1000 x g for 3 h at room temperature. Afterward, cells were resuspended and allowed to recover for 24 h in growth factor-containing medium. The transduction protocol was repeated a total of three times, and cells were assessed 1–2 wk later for IL-18 message.
Northern blot analysis
Total cellular RNA was isolated from RAW 264.7 cells using the RNAzol B reagent (Tel-Test, Friendswood, TX) according to the manufacturer’s instructions. RNA samples (20 µg) were size fractionated on 1.2% agarose/formaldehyde gels and transferred to nylon membranes. The filter was hybridized with radiolabeled IL-18 cDNA probe, washed, and autoradiographed at -70°C.
Cloning of the mouse IL-18 two promoter regions and construction of IL-18-CAT reporter plasmids
A mouse genomic DNA library in EMBL3 SP6/T7 vector (Clontech, Palo Alto, CA) was screened for cloning of the two promoter regions of IL-18 gene by using the 5' fragment of IL-18 cDNA (nt 1–524). Ten positive clones were selected, and their genomic DNAs were digested with XhoI. The products were subjected to Southern blot with another DNA probe (nt 1–194). By comparing with the restriction map and partial DNA sequencing, a clone of these products was identified as containing about 20 kb encompassing from the 5'-flanking region to exon 2 of IL-18 genome. To make reporter constructs, pCAT-basic plasmid (Promega, Madison, WI) was used to form p1-2686 for the 5'-flanking promoter or to form p2-2.3 for the intron 1 promoter. Deletion constructs of two promoter regions were obtained by digesting either p1-2686 or p2-2.3 plasmid using restriction enzymes or the PCR method. Site-directed mutants of ICSBP binding site or PU.1 binding site were constructed by PCR mutagenesis. Then, all constructs were confirmed by DNA sequencing.
Transient transfection and CAT assay
RAW 264.7 cells (1 x 107) were transfected by electroporation with 20 µg of CAT constructs in 250 µl of complete medium using Electro Cell Manipulator (BTX, San Diego, CA) at 230 V and 975 µF capacitance. Twenty-four hours later, transfected cells were further treated with LPS for 24 h, and then harvested. The cells were washed with ice-cold PBS, resuspended in 0.25 M Tris (pH 7.8), and subjected to three cycles of freezing and thawing. Cell lysates were heated for 10 min to inactivate CAT inhibitors and centrifuged. Then, the supernatant of the cell lysates was assayed for CAT enzyme activity by the TLC method (24). As an internal control for transfection efficiency, all cells were cotransfected with 5 µg of pCH110 plasmid (Pharmacia, Piscataway, NJ) for ß-galactosidase assay.
Oligonucleotide probes
Single-stranded oligonucleotides were annealed to form the
oligomers shown below. To prepare a probe for EMSA, each oligomer was
filled with [-32P]dCTP and three other
nonradiolabeled dNTPs by the Klenow fragment. The ICSBP and
PU.1 binding sites are underlined; mutations are italicized:
ICSBP, 5'-GGGAAGCTTGCTTTCACTTCTCCC-3' and
3'-TTCGAACGAAAGTGAAGAGGGGACAGG-5'; mICSBP,
5'-GGGAAGCTTGCTCCCACTTCTCCC-3' and
3'-TTCGAACGAGGGTGAAGAGGGGACAGG-3'; PU.1,
5'-GGGTTCTTCCTCATTCTT-3' and 3'-AAGAAGGAGTAAGAAGGG-3'; and
mPU.1, 5'-GGGTTCTCTCTCATTCTT-3' and
3'-AAGAGAGAGTAAGAAGGG-3'.
EMSA
Nuclear extracts for EMSA were prepared from RAW 264.7 cells as
previously described (25) with minor modifications. For
binding reactions, 7 µg of nuclear extract was incubated with
reaction buffer (10 mM Tris-HCl (pH 7.5), 50 mM NaCl, 1 mM DTT, 1 mM
EDTA, 5% glycerol, 2 µg of poly(dI-dC)·poly(dI-dC), and 1 µg of
BSA) in the presence or the absence of competitor or Ab for 20 min at
room temperature. Then, the radiolabeled probe (
20,000 cpm) was added
to the reaction mixture for an additional 10 min at room temperature.
Protein-DNA complexes were separated from the free probe by gel
electrophoresis on 6% polyacrylamide gels in 0.5x TBE buffer. The gel
was dried and analyzed by autoradiography.
RT-PCR
Total RNA was isolated from 0.5–5 x 106 cultured cells using Trizol (Life Technologies) as directed and was subjected to DNase I treatment (10 U for 30 min at 37°C; Boehringer Mannheim). Total RNA (1.0 µg) was reverse transcribed using Superscript II (Life Technologies), and 1/10th of the reaction was subjected to PCR using the following conditions: 94oC for 1 min, 55–65oC for 1 min, 72oC for 1 min for 30 cycles in a Perkin-Elmer thermocycler (GeneAmp 9600, Perkin-Elmer, Norwalk, CT). PCR primers for IL-18 were previously designed (3). Negative control reactions for RT-PCR contained RNA template that had not undergone RT. An aliquot (25 µl) of each 50-µl PCR reaction was run in a 1.5% agarose gel with ethidium bromide and photographed.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When RAW 264.7 macrophages were treated with LPS, IL-18 mRNA
expression was up-regulated in a dose-dependent manner (Fig. 1
A). IL-18 expression was
clearly detectable at 6 h and was maintained up to 24 h after
LPS treatment (Fig. 1B). Cycloheximide had no effect on
IL-18 expression at 9 h, suggesting that its expression was
directly induced by LPS rather than by other LPS-induced cytokines. In
untreated cells, constitutive expression of IL-18 mRNA was detected,
indicating that IL-18 gene expression is regulated by two different
mechanisms: constitutively and inducibly. A previous study by Tone et
al. (21) showed that murine IL-18 gene expression is
regulated by two distinct promoters located upstream of exon 1
(5'-flanking region) and upstream of exon 2 (intron 1), being analyzed
as an inducible or a constitutive promoter in terms of responsibilities
to LPS. We cloned two promoters: one is positioned from -2686 to +67
of the 5'-flanking region, and the other is positioned from
approximately -2300 to +72 of the intron 1 of murine IL-18 gene from a
BALB/c mouse-derived leukocyte genomic library. Each promoter region
was cloned into the upstream of the CAT gene in pCAT-Basic plasmid to
yield p1-2686 for the 5'-flanking promoter and p2-2.3 for the intron 1
promoter. To assay the inducibility by LPS, each p1-2686 and p2-2.3
plasmid was transfected into RAW 264.7 macrophages. Without LPS
stimulation, each promoter showed basal constitutive promoter
activities (Fig. 1C). However, in contrast to the previous
report, both promoters conferred LPS-inducible promoter activities,
although p1-2686 promoter exhibits a little higher LPS inducibility.
These results indicate that constitutive or LPS-inducible mouse IL-18
gene expression in RAW 264.7 macrophages is regulated simultaneously,
not by each promoter separately, even though the relative contribution
of each promoter to inducibility may be different.
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To identify the regulatory elements of the p1 promoter responsive
to LPS, sequential 5' deletion constructs of plasmid p1-2686 were
prepared (Fig. 2A). These
constructs were transfected into RAW 264.7 cells by electroporation,
and the cells were treated with or without LPS (1 µg/ml) for 24
h. As shown in Fig. 2B, deletion of the region from -2686
to -1528 did not affect the promoter activity significantly, but
deletion of the region from -1528 to -954 (p1-954) gave rise to a
significant decrease in LPS-induced transcriptional activity (70%
reduction) and in basal transcriptional activity (40% reduction),
indicating the existence of a positive element in this region. Also,
further deleting the promoter to -22 bp (p1-22) abolished the response
to LPS (70% reduction) as well as basal transcriptional activity (50%
reduction) compared with the p1-39 construct, suggesting the presence
of a positive regulatory element in the region from -39 to -22.
Transfection of the p1-438, p1-590, and p1-954 constructs resulted in
lower levels of CAT activity by LPS (each 50%) compared with the
p1-139, suggesting the presence of negative
cis-acting elements located between -438 and -139 bp.
Taken together, these results indicate that the two regions, positions
from -39 to -22 bp and from -1528 to -954 bp, contain elements that
are responsible for the LPS responsiveness as well as for the basal
transcriptional activity of the p1 promoter.
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Analysis of the sequence in the region from -39 to -22 revealed
the presence of a potential binding site for binding of
IFN-activated transcription factor, ICSBP, or IRF-E, which differed
by 1 bp from their consensus sequence (26, 27). To
determine whether this site was responsible for the LPS inducibility of
the proximal region of p1 promoter identified above, site-directed
mutagenesis of the ICSBP binding site
(TGCTTTCACTTCTC
TGCTCCCACTTCTC) was
introduced into each p1-39 and p1-2686 to generate the plasmid p1-m39
(mICSBP) and p1-m2686 (mICSBP), respectively (Fig. 3A). The constructs were then
transiently transfected into RAW 264.7 cells, and their activity was
examined following 24-h treatment with LPS (1 µg/ml). As shown in
Fig. 3B, RAW 264.7 cells transfected with the p1-m39
(mICSBP) showed a significant 2- to 3-fold decrease in CAT activity by
LPS compared with that of cells transfected with the wild-type
construct. The reduction of CAT activity was more prominent when
mutation was introduced in the full-length p1 promoter (3- to
4-fold reduction). These results indicate that the ICSBP binding site
is essential for p1 promoter activity.
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To determine whether LPS induces DNA binding activity to a
putative ICSBP binding site of the p1 promoter, we performed EMSA using
an oligonucleotide probe encompassing the ICSBP binding site. Control
nuclear extract of RAW 264.7 cells showed minimal binding activity.
Treatment with LPS, however, markedly increased the formation of a DNA
binding complex (Fig. 4A).
When a 100-fold excess of a wild-type probe was added, it efficiently
competed with the protein-DNA complex, whereas the probe containing a
mutated ICSBP binding sequence did not compete. LPS-induced ICSBP
binding was time dependent, with maximal binding at 3–6 h after
treatment (Fig. 4B). The ICSBP binding complex was also
detected at 0 h in longer exposure (data not shown). In
addition, when supershift assays were performed using Abs against ICSBP
or IRF-1, retardation of the protein-DNA complex was seen only by the
addition of ICSBP, but not IRF-1 (Fig. 4C).
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Next, p1 promoter was cotransfected with ICSBP expression vector
(28) to determine the direct activation of p1 promoter by
ICSBP. As shown in Fig. 5, cotransfection
with ICSBP expression vector increased p1 promoter activity (
2-fold)
compared with cotransfection with control vector. Taken together, these
results show that ICSBP binding activity is critical for inducing p1
promoter activity.
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To identify the important regulatory elements responsible for the
constitutive or LPS activation of p2 promoter described above, a series
of deletion mutants linked to CAT reporter gene were constructed from
the full-length p2-2.3 plasmid (Fig. 6A). These constructs were
transiently transfected into RAW 264.7 cells, and the expression of CAT
was measured in the presence or the absence of LPS. As shown in Fig. 6B, RAW 264.7 cells transfected with the p1-31 construct
were almost sufficient to confer basal level activity, but they showed
the reduced relative LPS inducibility (<2 fold). Transfection of the
pC-13 construct resulted in a significant decrease in CAT activity by
medium (70% reduction) or LPS (70% reduction) compared with the pC-31
construct, suggesting that the region from -31 to -13 contains the
essential transcription factor binding sites for p2 promoter activity.
As shown in the case of p1 promoter, potential negative regulatory
sites are located in the region from -72 to -461 and the region from
-571 to -1600.
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Sequence analysis of the region from -31 to -13 for
transcription factor binding revealed that this region contained a
potential binding site for PU.1 (TTCCTC). To determine whether the
putative PU.1 binding site in this region is functional for the
constitutive or LPS-inducible activation of p2 promoter, site-specific
mutagenesis of the PU.1 binding site (TTCCTCTCTCTC) was
introduced to generate the plasmid p2-m31 (mPU.1; Fig. 7A). RAW 264.7 cells
transfected with the plasmid containing the mutated PU.1 binding site
showed a significant decrease in LPS-induced CAT activity as well as
basal activity compared with cells transfected with the wild-type
construct (Fig. 7B). When the same PU.1 mutation was
introduced into the full-length promoter construct p2-2.3 (p2-m2.3) or
p2-571 (p2-m571), promoter activity was also substantially reduced.
Therefore, the PU.1 binding site plays an important role in p2 promoter
activation.
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Next, to learn whether LPS induced DNA binding activity to a
putative PU.1 binding site of p2 promoter, we performed EMSA for PU.1
binding with nuclear extracts prepared from RAW 264.7 cells either
unstimulated or treated with LPS. Although control nuclear extract
showed a constitutive binding activity, treatment with LPS (1 µg/ml)
increased PU.1 binding activity (Fig. 8A). The specificity of
increased binding activity by LPS was demonstrated by competition
experiments with a 20- or 100-fold molar excess of wild-type probe. An
oligonucleotide probe containing the mutated sequences, however, did
not compete for binding, suggesting that the integrity of the PU.1
binding site was required for the binding activity. Dose-dependant
binding of PU.1 in response to LPS was confirmed as shown in Fig. 8B, comparing constitutive Oct-1 binding as the internal
control. As seen in the case of ICSBP binding, PU.1 binding was maximal
at 3–6 h after treatment with LPS (Fig. 8C). The identity
of nuclear protein binding to this site was confirmed by supershift
assay with specific Ab against PU.1. The addition of PU.1-specific Abs
to LPS-treated nuclear extracts resulted in a formation of supershifted
complex (Fig. 8D).
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Constitutive IL-18 expression was detected in normal mouse
macrophages and neutrophils (Fig. 9), but
there was no IL-18 expression in the PU.1 null neutrophil cell line
503, strongly indicating that PU.1 has an essential role in
constitutive expression of IL-18. In addition, transfection of PU.1
into 503 cells (503-PU.1) restored constitutive IL-18 expression,
whereas transfection of M-CSF receptor (503-MR) did not restore it.
Restoration of IL-18 expression was also observed when primary liver
cells from PU.1 knockout mice were transfected with PU.1.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LPS inducibility of IL-18 seems to be different depending on cell
types. In Kupffer cells and peritoneal cells, IL-18 did not respond to
LPS (3), but, IL-18 was induced by LPS in RAW cells as
shown in our and Tone’s studies (21) and in mouse
splenocytes (29). However, there are some differences
between our results and Tone’s findings. First, two promoters showed
LPS inducibility in our results (Figs. 1
C and
6B), even though the inducibility of p2 promoter
(constitutive promoter in Tone’s study) was slightly less than that of
p1 promoter. Second, the relative basal promoter activities of the two
promoters are different. In our results, the relative basal activities
of the two promoters were relatively equal, but much higher in p2
promoter (constitutive promoter) in the case of Tone’s study. It is
not clear yet what caused these differences between the two studies,
which used similar promoter constructs and the same cell line, but
Northern blots supported these differences: more LPS inducibility in
our study and strong basal expression in Tone’s study.
PU.1, the ETS transcription factor, is expressed exclusively in myeloid
and B cells. PU.1 is involved in the regulation of promoters for the
genes encoding receptors for M-CSF and GM-CSF. Studies from PU.1
gene-disrupted mice indicated that it is involved in M-CSF- and
GM-CSF-mediated proliferation and development. These results indicate
that PU.1 functions in the differentiation of multipotential lymphoid
and myeloid progenitors. PU.1 binds to the consensus DNA sequence of
TTCCTC and is involved in the expression of numerous genes that
regulate B cell maturation and macrophage differentiation. It is
essential for transcription of Ig light chains, J chains, and the
macrophage scavenger receptors (30). For transcriptional
activation of PU.1, phosphorylation of serine 148 in PU.1, such as by
casein kinase II (31), is required, implying that a proper
phosphorylation state and conformation are important for PU.1 activity.
It was also reported that LPS and IFN- induce DNA binding of PU.1
through a post-translational mechanism(s) in murine tissue macrophages
(32).
Deletion and mutagenesis studies (Figs. 6 and 7) indicate that the PU.1
binding site is critical for p2 promoter activity, especially in
constitutive activation of p2 promoter. Relative LPS inducibility of
p2-31 construct was reduced (<2-fold) compared with that of p2-2.3,
and introducing a PU.1 mutation or deletion mutation of the p2-31
construct appeared to affect constitutive expression to a much greater
degree than inducible expression. Furthermore, studies using PU.1 null
cells (Fig. 9) demonstrated that PU.1 has an essential role in
constitutive expression of IL-18. However, it cannot be ruled out that
PU.1 also has a minimal role in LPS inducibility, as shown in the case
of minimal inducibility of p2-31 construct and its binding activity
induced by LPS treatment (Fig. 8).
The deletion and mutagenesis studies of p1 promoter showed that ICSBP
is also involved in both basal and inducible activities of p1 promoter.
However, mutation of the ICSBP element seemed to affect inducible
expression of p1-39 more than constitutive expression (Figs. 2 and 3),
suggesting that ICSBP has an essential role in inducible expression of
IL-18 with a minor role in constitutive expression. ICSBP has been
known as a transcriptional repressor involved in negative regulation of
transcription (28). However, recent reports demonstrated
that ICSBP is essential for IL-12 p70 (33) and p40
(34) induction. In this regard, our results of
cotransfection experiment (Fig. 5) are consistent with these results
(33, 34) describing ICSBP as an enhancer of IL-12
production. ICSBP is expressed exclusively in immune cells, such as
monocytes and B cells. It has three functional domains: a DNA binding
domain, a transcriptional repressor domain, and a domain that enables
the association with other IRFs (35). This association
domain is conserved among some IRF members and is located near the
carboxyl terminus between residues 200 and 377. Therefore, ICSBP might
have different effects in different immune cells depending on the
milieu of IRFs that are associated with it (36). Our
unpublished results indicated that other stimuli, such as IFN-,
showed a slightly different regulation of promoter activity employing
other transcription factor complexes, including IRF-1 in addition to
ICSBP.
In addition, several studies (30, 36, 37) reported that PU.1 also interacts with the IRF family to increase target gene expression. This complex includes IRF-1, IRF-4, ICSBP, PU.1 interaction partner, and PU.1. This interaction is controlled by stimuli-induced phosphorylation of these proteins, such as serine 148 phosphorylation in PU.1. It implies a possible interaction between ICSBP in p1 promoter and PU.1 in p2 promoter, but it seems unlikely because there is no substantial difference between Northern analysis and promoter analysis in terms of LPS inducibilities. However, further studies are required to determine the possible interaction between the two promoters using different stimuli or a construct containing both promoters.
Regulation of IL-18 gene expression demonstrates a unique aspect in cytokine gene expression, structurally and functionally. Also, post-transcriptional and translational events, including processing with ICE, are another limiting point for the production of mature IL-18. Further understanding of the relationship between these cascade events will reveal the controlling machinery for IL-18 expression during inflammation and other immune responses. In conclusion, expression of the IL-18 gene is controlled by two promoters that are inducible by LPS. ICSBP (for p1 promoter) and PU.1 (for p2 promoter) are critical factors for IL-18 promoter activity, performing dominant regulatory roles in inducible and constitutive expression of IL-18, respectively.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Inpyo Choi, Immune Cell Signal Transduction RU, Korea Research Institute of Bioscience and Biotechnology, Eoun-Dong 52, Yusong, Taejon 305-333, Republic of Korea. E-mail address:
3 Abbreviations used in this paper: ICE, IL-1ß-converting enzyme; ICSBP, IFN consensus sequence binding protein; IRF-1, IFN regulatory factor-1; CAT, chloramphenicol acetyltransferase.
Received for publication December 1, 1998. Accepted for publication June 4, 1999.
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M. Witcher, H. Y. Shiu, Q. Guo, and W. H. Miller Jr Combination of retinoic acid and tumor necrosis factor overcomes the maturation block in a variety of retinoic acid-resistant acute promyelocytic leukemia cells Blood, November 15, 2004; 104(10): 3335 - 3342. [Abstract] [Full Text] [PDF]
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 S. Suzuki, K. Honma, T. Matsuyama, K. Suzuki, K. Toriyama, I. Akitoyo, K. Yamamoto, T. Suematsu, M. Nakamura, K. Yui, et al. From the Cover: Critical roles of interferon regulatory factor 4 in CD11bhighCD8{alpha}- dendritic cell development PNAS, June 15, 2004; 101(24): 8981 - 8986. [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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A. C. Morrison, C. B. Wilson, M. Ray, and P. H. Correll Macrophage-Stimulating Protein, the Ligand for the Stem Cell-Derived Tyrosine Kinase/RON Receptor Tyrosine Kinase, Inhibits IL-12 Production by Primary Peritoneal Macrophages Stimulated with IFN-{gamma} and Lipopolysaccharide J. Immunol., February 1, 2004; 172(3): 1825 - 1832. [Abstract] [Full Text] [PDF]
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M. Alter-Koltunoff, S. Ehrlich, N. Dror, A. Azriel, M. Eilers, H. Hauser, H. Bowen, C. H. Barton, T. Tamura, K. Ozato, et al. Nramp1-mediated Innate Resistance to Intraphagosomal Pathogens Is Regulated by IRF-8, PU.1, and Miz-1 J. Biol. Chem., November 7, 2003; 278(45): 44025 - 44032. [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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N. Takeda, M. Arima, N. Tsuruoka, S. Okada, M. Hatano, A. Sakamoto, Y. Kohno, and T. Tokuhisa Bcl6 Is a Transcriptional Repressor for the IL-18 Gene J. Immunol., July 1, 2003; 171(1): 426 - 431. [Abstract] [Full Text] [PDF]
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 M. Jin, H. J. Jung, J. J. Choi, H. Jeon, J. H. Oh, B. Kim, S. S. Shin, J. K. Lee, K. Yoon, and S. Kim Activation of Selective Transcription Factors and Cytokines by Water-Soluble Extract from Lentinus lepideus Experimental Biology and Medicine, June 1, 2003; 228(6): 749 - 758. [Abstract] [Full Text] [PDF]
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B. J. Barnes, A. E. Field, and P. M. Pitha-Rowe Virus-induced Heterodimer Formation between IRF-5 and IRF-7 Modulates Assembly of the IFNA Enhanceosome in Vivo and Transcriptional Activity of IFNA Genes J. Biol. Chem., May 2, 2003; 278(19): 16630 - 16641. [Abstract] [Full Text] [PDF]
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 J.-M. Wang, M.-Z. Lai, and H.-F. Yang-Yen Interleukin-3 Stimulation of mcl-1 Gene Transcription Involves Activation of the PU.1 Transcription Factor through a p38 Mitogen-Activated Protein Kinase-Dependent Pathway Mol. Cell. Biol., March 15, 2003; 23(6): 1896 - 1909. [Abstract] [Full Text] [PDF]
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D. W. Mullins, R. S. Martins, and K. D. Elgert Tumor-Derived Cytokines Dysregulate Macrophage Interferon-{gamma} Responsiveness and Interferon Regulatory Factor-8 Expression Experimental Biology and Medicine, March 1, 2003; 228(3): 270 - 277. [Abstract] [Full Text] [PDF]
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J. A. Gracie, S. E. Robertson, and I. B. McInnes Interleukin-18 J. Leukoc. Biol., February 1, 2003; 73(2): 213 - 224. [Abstract] [Full Text] [PDF]
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 T. Nomura, I. Kawamura, K. Tsuchiya, C. Kohda, H. Baba, Y. Ito, T. Kimoto, I. Watanabe, and M. Mitsuyama Essential Role of Interleukin-12 (IL-12) and IL-18 for Gamma Interferon Production Induced by Listeriolysin O in Mouse Spleen Cells Infect. Immun., March 1, 2002; 70(3): 1049 - 1055. [Abstract] [Full Text] [PDF]
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Y. Toda, J. Tsukada, M. Misago, Y. Kominato, P. E. Auron, and Y. Tanaka Autocrine Induction of the Human Pro-IL-1{beta} Gene Promoter by IL-1{beta} in Monocytes J. Immunol., February 15, 2002; 168(4): 1984 - 1991. [Abstract] [Full Text] [PDF]
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 C Hanck, T Manigold, U Bocker, M Kurimoto, C B Kolbel, M V Singer, and S Rossol Gene expression of interleukin 18 in unstimulated peripheral blood mononuclear cells of patients with alcoholic cirrhosis Gut, July 1, 2001; 49(1): 106 - 111. [Abstract] [Full Text] [PDF]
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R. Vankayalapati, B. Wizel, D. L. Lakey, Y. Zhang, K. A. Coffee, D. E. Griffith, and P. F. Barnes T Cells Enhance Production of IL-18 by Monocytes in Response to an Intracellular Pathogen J. Immunol., June 1, 2001; 166(11): 6749 - 6753. [Abstract] [Full Text] [PDF]
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S. Marecki, C. J. Riendeau, M. D. Liang, and M. J. Fenton PU.1 and Multiple IFN Regulatory Factor Proteins Synergize to Mediate Transcriptional Activation of the Human IL-1{{beta}} Gene J. Immunol., June 1, 2001; 166(11): 6829 - 6838. [Abstract] [Full Text] [PDF]
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E. Seki, H. Tsutsui, H. Nakano, N. M. Tsuji, K. Hoshino, O. Adachi, K. Adachi, S. Futatsugi, K. Kuida, O. Takeuchi, et al. Lipopolysaccharide-Induced IL-18 Secretion from Murine Kupffer Cells Independently of Myeloid Differentiation Factor 88 That Is Critically Involved in Induction of Production of IL-12 and IL-1{{beta}} J. Immunol., February 15, 2001; 166(4): 2651 - 2657. [Abstract] [Full Text] [PDF]
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S. Sugama, Y. Kim, H. Baker, C. Tinti, H. Kim, T. H. Joh, and B. Conti Tissue-Specific Expression of Rat IL-18 Gene and Response to Adrenocorticotropic Hormone Treatment J. Immunol., December 1, 2000; 165(11): 6287 - 6292. [Abstract] [Full Text] [PDF]
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Y.-M. Kim, J. Y. Im, S. H. Han, H. S. Kang, and I. Choi IFN-{gamma} Up-Regulates IL-18 Gene Expression Via IFN Consensus Sequence-Binding Protein and Activator Protein-1 Elements in Macrophages J. Immunol., September 15, 2000; 165(6): 3198 - 3205. [Abstract] [Full Text] [PDF]
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 D. Cho, H. Song, Y. M. Kim, D. Houh, D. Y. Hur, H. Park, D. Yoon, K. H. Pyun, W. J. Lee, M. Kurimoto, et al. Endogenous Interleukin-18 Modulates Immune Escape of Murine Melanoma Cells by Regulating the Expression of Fas Ligand and Reactive Oxygen Intermediates Cancer Res., May 1, 2000; 60(10): 2703 - 2709. [Abstract] [Full Text]
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M. Rehli, A. Poltorak, L. Schwarzfischer, S. W. Krause, R. Andreesen, and B. Beutler PU.1 and Interferon Consensus Sequence-binding Protein Regulate the Myeloid Expression of the Human Toll-like Receptor 4 Gene J. Biol. Chem., March 24, 2000; 275(13): 9773 - 9781. [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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V. T. Nguyen and E. N. Benveniste Involvement of STAT-1 and Ets Family Members in Interferon-gamma Induction of CD40 Transcription in Microglia/Macrophages J. Biol. Chem., July 28, 2000; 275(31): 23674 - 23684. [Abstract] [Full Text] [PDF]
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P. Rieske and J. M. R. Pongubala AKT Induces Transcriptional Activity of PU.1 through Phosphorylation-mediated Modifications within Its Transactivation Domain J. Biol. Chem., March 9, 2001; 276(11): 8460 - 8468. [Abstract] [Full Text] [PDF]
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