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Blood, Vol. 95 No. 8 (April 15), 2000:
pp. 2715-2718
BRIEF REPORT
Constitutive activation of LIL-Stat in adult T-cell leukemia
cells
Junichi Tsukada,
Yoko Toda,
Masahiro Misago,
Yoshiya Tanaka,
Philip E. Auron, and
Sumiya Eto
From the First Department of Internal Medicine, School of Medicine,
and School of Health Sciences, University of Occupational and
Environmental Health, Kitakyushu, Japan; and The New England Baptist
Bone & Joint Institute, Beth Israel Deaconess Medical Center and
Department of Medicine, Harvard Medical School, Boston, MA.
 |
Abstract |
The activation status of a recently identified STAT (signal
transducers and activators of transcription) factor, LIL-Stat (lipopolysaccharide [LPS]/IL-1-inducible Stat) in adult T-cell leukemia (ATL) cells was investigated by electrophoretic mobility shift
assays using nuclear extracts of leukemic cells from 7 patients with
ATL and a GAS (gamma interferon activation site)-like element termed
LILRE (LPS/IL-1-responsive element), which is found in the human
prointerleukin 1 (IL1B) gene. Spontaneous DNA binding of
LIL-Stat was observed in all ATL cells examined. However, in normal
human peripheral lymphocytes, DNA binding of LIL-Stat was detected only
after stimulation with IL-1. These results demonstrated that LIL-Stat
is constitutively activated in ATL cells. Furthermore, our transient
transfection studies using LILRE chloramphenicol acetyltransferase
(CAT) reporters argue that LIL-Stat in ATL cells functions as a
transcriptional activator through binding to the LILRE in the
IL1B gene.
(Blood. 2000;95:2715-2718)
© 2000 by The American Society of Hematology.
| |
Introduction |
Binding of many cytokines to their cognate receptors
immediately activates Jak tyrosine kinases and their substrates;
namely, STAT (signal transducers and activators of transcription) DNA binding proteins. The activated STAT proteins dimerize and are translocated to the nucleus to transactivate genes by binding to
variations on the gamma interferon (IFN- ) activation site (GAS),
which was initially reported to bind the IFN--induced Stat
1.1,2 Recently, transformation of T cells by human T-cell leukemia virus type I (HTLV-I) has been reported to be associated with
constitutive activation of the Jak-STAT pathway.3,4 Stat3
and Stat5, which become activated in normal T cells in response to
IL-2, have been demonstrated to be constitutively activated in
HTLV-I-transformed cells.3 Furthermore, Takemoto et
al5 have observed constitutive activation of Stat1, Stat3,
and Stat5 in leukemic cells of patients with adult T-cell leukemia
(ATL), an aggressive T-cell malignancy induced by HTLV-I infection.
We have recently demonstrated that both lipopolysaccharide (LPS) and
IL-1 immediately activate a common novel STAT factor.6 This
LPS/IL-1 inducible factor (LIL-Stat) binds a GAS-like sequence (TTCCTGAGA) termed LILRE (LPS and IL-1 responsive element) in the human
prointerleukin 1 (IL1B) gene and is recognized by an antibody (Ab) raised to the N-terminus of Stat1 (anti-Stat1N Ab), but
not by those specific for either the C terminus of Stat1 (anti-Stat1C Ab) or any other GAS-binding STAT. Moreover, the DNA-binding activity of this protein has been shown to be specifically inhibited by phosphotyrosine, suggesting that phosphotyrosine mediates the obligate
dimerization required for STAT DNA binding. Analysis of DNA binding
specificity has demonstrated that the LIL-Stat possesses a novel
GAS-like binding activity that contrasts with that of other STATs in a
requirement for a G residue at position 8 (LILRE;
TTCCTGAGA). The existence of such a factor relates the
signaling pathway for IL-1 and LPS receptors to other cytokine receptors that mediate signaling via the immediate activation of STAT
transcriptional factors. Interestingly, a recent study7 has
demonstrated constitutive activation of LIL-Stat in acute myelocytic
leukemia (AML) cells.
In this study, we investigated LIL-Stat activation status in ATL cells
by electrophoretic mobility shift assay (EMSA) using a radiolabeled
LILRE probe and ATL cell nuclear extracts. The functional role of
LIL-Stat in ATL cells was further assessed by transient transfection
studies using LILRE chloramphenicol acetyltransferase (CAT) reporters.
| |
Study design |
Oligonucleotides
The nucleotide sequences of oligonucleotides used in this study were
as follows (the core recognition sequence of each oligonucleotide is
underlined): LILRE,
5'-AGCTTATAAGAGGTTTCACTTCCTGAGAGTCGA-3'; mutated LILRE (LILRE/mGAS),
5'-AGCTTATAAGAGGTT- TCACTTCCTGAGcGTCGA-3'; GAS derived from the FcRI gene,
5'-CGATCGAGATGTATTTCCCAGAAAAGTCGA-3'; mutated
GAS
(mGAS),5'-CGATCGAGATGTATggCCCAGAcAAGTCGA-3';
hSIE (high-affinity sis-inducible element),
5'-AGCTTGTGCATTTCCCGTAAATCTTGTCGTCGA-3'; SIE,
5'-AGCTTGTGCAGTTCCCGTCAATCTTGTCGTCGA-3'. LILRE
corresponds to positions  2863 to 2841 of the IL1B
gene (GenBank accession no. L06808).
Antibodies
The amino-terminus-specific Stat1N Ab (anti-Stat1N Ab) was purchased
from Transduction Laboratories (Lexington, KY). This Ab was raised
against the amino-terminal 194 amino acids of Stat1. The carboxyl
terminus-specific Stat1C (anti-Stat1C Ab) and antiphosphotyrosine Ab
(anti-p-tyr Ab) were purchased from Santa Cruz Biotechnology Inc (Santa
Cruz, CA). Anti-Stat1C Ab was raised against a peptide containing amino
acids 688 to 700 of Stat1.
Cells and nuclear extracts
Blood samples were obtained from 7 patients with acute ATL after
they gave their informed consent. Their peripheral white blood cell
(WBC) counts ranged from 35 000 to 73 500/µL. More than 90% of the
peripheral WBCs were leukemic cells. The diagnosis of acute ATL was
made on the basis of clinical features, hematologic findings, and the
presence of the monoclonal integration of HTLV-I provirus in the
leukemic cells. Peripheral blood mononuclear cells were separated from
patients' blood by Ficoll-Hypaque density gradient centrifugation. The
cell population consisted of more than 95% ATL cells, as determined by
both the morphologic characteristics of cells on Wright-Giemsa-stained
slides and flowcytometric cell surface marker analysis using
fluorescein isothiocyanate (FITC)- or phycoerythrin-conjugated
monoclonal antibodies. Normal human lymphocytes were obtained from
healthy blood donors after they gave their informed consent.
Nuclear extracts were prepared from ATL cells, normal human peripheral
lymphocytes, and human THP-1 monocytic leukemic cells, as previously
described.8 Freshly isolated ATL cells and lymphocytes were
used in this study. In some experiments, lymphocytes were stimulated
with 10 ng/mL of IL-1 for 15 minutes. Lymphocytes preactivated by
phytohemagglutinin (PHA) treatment were stimulated with 10 ng/mL of
IL-2 for 15 minutes. THP-1 cells (JCRB 0112; Health Science Research
Resources Bank, Osaka, Japan) were cultured as previously
described.8 THP-1 cells were stimulated by incubating them
in the presence of 1 µg/mL of LPS for 15 minutes. All nuclear extracts were prepared in the presence of 1 mmol/L ZnCl2, 1 mmol/L sodium orthovanadate, and 10 mmol/L NaF to inhibit phosphatase activities.
EMSA
32P-labeled LILRE, hSIE, and SIE probes were used in
this study. Binding reactions were performed as previously described,
followed by analysis on a 4% polyacrylamide gel using
0.5 × TBE (45 mmol/L Tris-borate and 1 mmol/L EDTA) as the
running buffer.6 Unlabeled competitor oligonucleotides were
used at a 50-fold molar excess over the radiolabeled probe. In EMSA
experiments using Abs, nuclear extracts were incubated with either
anti-Stat1N Ab, anti-Stat1C Ab, or anti-p-tyr Ab at 4°C for 1 hour.
Plasmids
Either LILRE or LILRE/mGAS was inserted into a CAT reporter
containing a minimal (59 to +105) murine c-fos promoter
(fos/CAT).9 A plasmid 3MHT contains the IL1B
gene promoter sequence between 131 and +12 (HT fragment)
ligated to CAT as previously described.8 Constructs
LILRE/3MHT and LILREmGAS/3MHT were generated by inserting LILRE and
LILRE/mGAS, respectively into the 3MHT. These constructs were verified
by sequencing.
Transfection and chloramphenicol acetyltransferase assay
Transfection of ATL cells was carried out by the DEAE-dextran method
as described previously.8 This DEAE-dextran method does not
induce the endogenous IL1B gene in ATL cells (data not shown).
ATL cells (1 × 107 cells per plate) were
transfected with 10 µg of plasmids. At 36 hours after transfection,
cells were harvested. The CAT assays were carried out by a liquid
scintillation method as described previously.8
| |
Results and discussion |
Nuclear extracts obtained from leukemic cells of 2 patients with ATL
generated several complexes with the LILRE probe (Figure 1A and B). One of these complexes (Figure
1A and B; arrows) was recognized by anti-Stat1N Ab (lane 2), but not by
anti-Stat1C Ab (lane 3). This complex was abrogated by the addition of
antiphosphotyrosine Ab (anti-p-tyr Ab) (lane 8). Pearse et
al10 reported that an A-to-C mutation at position 9 of the
GAS sequence (TTCCNNNAA) resulted in a significant
reduction in Stat 1 binding. In this study, a single point mutation at
position 9 of the GAS-like sequence within the LILRE (LILRE/mGAS)
significantly reduced the affinity of the LILRE for the complex
(comparison of lane 6 with lane 7). In addition, a 50-fold molar excess
of unlabeled bona fide GAS DNA competed for the complex (lane 5). These
results indicated spontaneous binding of LIL-Stat to LILRE in ATL
cells. We further investigated DNA binding of LIL-Stat in leukemic
cells of 7 patients with ATL. As shown in lanes 3 to 10 of Figure 1C,
spontaneous binding of LIL-Stat was observed in leukemic cells of all
the patients with ATL examined. Moreover, the LIL-Stat/LILRE complex in
LPS-stimulated THP-1 cells (lane 1 of Figure 1C) possessed the same
electrophoretic mobility as that seen in ATL cells, supporting our
argument that LIL-Stat is activated in ATL cells.
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| Fig 1.
Constitutive activation of LIL-Stat in leukemic cells of
patients with ATL.
LILRE was used as a radiolabeled probe. Nuclear extracts were prepared
from ATL cells (A, B, and lanes 3 to 10 of C) and LPS-stimulated THP-1
monocytic leukemia cells (lanes 1 and 2 of C). The double-stranded
oligonucleotides used in this study were described in "Materials and
methods." Unlabeled competitor oligonucleotides were used at a
50-fold molar excess over radiolabeled LILRE probe. D shows the
enhancer activity of LILRE in leukemic cells of 2 patients with ATL.
Transfection of CAT reporters into ATL cells and CAT assays were
carried out as described in "Materials and methods." The CAT data
were normalized to the average activity elicited by either
fos/CAT or 3M. Error bars represent SDs from triplicate
cultures.
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|
The LILRE is located within the previously identified 406-base pair
(bp) enhancer of the human IL1B gene. Therefore, we further examined the enhancer activity of the LILRE in transiently transfected leukemic cells obtained from 2 patients with ATL (Figure 1D). A single
copy of the LILRE (LILRE/fosCAT) was inserted into an enhancer-dependent CAT construct (fos/CAT) by using the minimal murine c-fos promoter. As shown in Figure 1D, the presence of a
single copy of LILRE (LILRE/fosCAT) resulted in approximately 2-fold increase in CAT activity in both cases. The transcriptional activity of the LILRE was significantly inhibited by a single point
mutation of the LILRE (LILREmGAS/fosCAT). Furthermore, a 3MHT
CAT vector containing the IL1B promoter sequence (HT fragment; 131 to +12) was used in this study. Constructs LILRE/3MHT and LILREmGAS/3MHT were generated by inserting LILRE and LILRE/mGAS, respectively into the 3MHT. As shown in Figure 1D, although the presence of HT IL1B promoter sequence caused only a little
increase in CAT activity, LILRE/3MHT containing a single copy of LILRE upstream of the IL1B gene promoter sequence generated
significantly higher CAT activity than did 3MHT in both cases. A single
point mutation of the LILRE (LILREmGAS/3MHT) caused almost complete loss of the transcriptional activity. Thus, the results obtained from
this study argue that LIL-Stat in ATL cells can function as a
transcriptional activator through binding to the LILRE in the
IL1B gene.
In a previous study, we showed that IL-1 induced DNA binding of
LIL-Stat in murine EL4 thymoma cells.6 However, in contrast to the results obtained from ATL cells, no spontaneous DNA binding of
LIL-Stat was detected in EL4 cells.6 On the other hand, Tuyt et al7 observed neither spontaneous nor inducible
LIL-Stat DNA binding in fully differentiated monocytes and
granulocytes. In this study, we carried out EMSA studies by using
nuclear extracts of unstimulated peripheral lymphocytes obtained from 5 healthy blood donors to elucidate the presence and activation status of LIL-Stat in normal human peripheral lymphocytes. As shown in Figure 2A (lanes 2 to 6), unstimulated normal
lymphocytes did not show LIL-Stat DNA binding activity. Moreover, in
contrast to ATL cells in which LIL-Stat was spontaneously bound to
LILRE, DNA binding of LIL-Stat was detected only after stimulation with
IL-1 in normal peripheral lymphocytes (Figure 2B).
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| Fig 2.
LIL-Stat, which specifically recognizes the LILRE
sequence, is not constitutively activated in normal lymphocytes.
A, LILRE was used as a radiolabeled probe. Nuclear extracts prepared
from unstimulated lymphocytes of 5 healthy donors were used in lanes 2 to 6. As a control, an ATL cell nuclear extract was used in lane 1. B,
LILRE was used as a radiolabeled probe. Nuclear extracts were obtained
from untreated (lanes 1 and 3) and IL-1-treated (lanes 2 and 4)
lymphocytes of 2 healthy donors. C, An ATL cell nuclear extract and
radiolabeled hSIE (lanes 1 to 5) and SIE (lanes 7 to 11) probes were
used. As a control study (lane 6), the ATL cell nuclear extract was
incubated with a radiolabeled LILRE probe. D, LILRE (lanes 1 and 2) and
hSIE (lanes 3 and 4) were used as radiolabeled probes. Lymphocytes
preactivated by PHA treatment were not stimulated (lanes 1 and 3) or
were stimulated with IL-2 (lanes 2 and 4). EMSAs were conducted as
described in Figure 1.
|
|
Takemoto et al5 observed constitutive activation of Stat1
in ATL cells by EMSAs using an Ab raised against the N terminus of
Stat1 and a radiolabeled hSIE probe. In this study, we examined the
abilities of hSIE and SIE to bind LIL-Stat by EMSAs using radiolabeled
hSIE and SIE probes and an ATL cell nuclear extract (Figure 2C). This
nuclear extract showed spontaneous LIL-Stat binding to LILRE (lane 6 of
Figure 2C). As shown in lanes 1 to 3, incubation of the ATL cell
nuclear extract with a radiolabeled hSIE probe generated a DNA/protein
complex (arrow) recognized by both anti-Stat1C and anti-Stat1N Abs.
Moreover, the complex was not competed for by LILRE (lane 4). A similar
protein/DNA complex recognized by both anti-Stat1C and anti-Stat1N Abs
(arrow; lanes 7 to 11 of Figure 2C) was observed by using a
radiolabeled SIE probe. The SIE/protein complex was not competed for by
LILRE (lane 10). These results showed that LIL-Stat does not bind to either hSIE or SIE. This argument is further supported by our previous
report, which has demonstrated that mutation of a G residue to any
other residue at position 8 of the LILRE (TTCCTGAGA) significantly reduced affinity of the LILRE for LIL-Stat.6 In this regard, neither the hSIE (TTCCCGTAA) nor the
SIE (TTCCCGTCA) contains a G residue at position 8. On
the other hand, when ATL cell nuclear extracts and a radiolabeled LILRE
probe were used, LILRE did not bind a protein recognized by anti-Stat1C
Ab (lane 3 of Figure 1A and lane 3 of Figure 1B). These results show
that LILRE does not efficiently bind Stat1, and further suggest that
the LIL-Stat/LILRE complex does not contain Stat1. In agreement with
this argument, we have previously reported that Stat1 derived from
IFN--treated U937 monocytic cells cannot efficiently bind to
LILRE.6 However, because it is possible that LIL-Stat
heterodimerizes with a protein(s) that binds to LILRE, further studies
are required for characterization of the LIL-Stat.
IL-2 signaling requires ligand-induced heterodimerization of the IL-2
receptor (IL-2R) and chain cytoplasmic domains.11 The and chains of IL-2R are used in common by IL-15 and
IL-2.12 Several studies have reported that IL-2/IL-15
signaling pathway plays an important role in proliferation of ATL cells
and HTLV-I-transformed T cells.13-17 Migone et
al3 have shown that the IL-2R chain is constitutively
associated with Jak3 in HTLV-I-transformed MT-2 T cells. They further
observed constitutive association of the IL-2R chain with both the
chain and Jak3 in MT-2 cells. In addition, granulocyte-colony
stimulating factor (G-CSF)18 and IL-419 have
also been shown to induce proliferation of leukemic cells in some
patients with ATL. We have previously demonstrated that IL-4 does not
activate LIL-Stat.6 Moreover, our EMSA using lymphocytes
showed that IL-2 did not activate LIL-Stat, but induced formation of a
protein/hSIE complex (Figure 2D; arrow). However, it remains unknown
whether G-CSF activates LIL-Stat. On the other hand, elevated serum
levels of IL-620 and the IL-6 signal transducer gp13021 have been reported in ATL patients. The fact that
LIL-Stat is activated by IL-6 as well as IL-16 may suggest
the possibility that increased production of these factors causes
constitutive activation of LIL-Stat in ATL cells.
On the basis of our results obtained from this study, we conclude that
LIL-Stat is constitutively activated in ATL cells. Spontaneous
IL1B gene expression has been observed in leukemic cells of a
considerable number of patients with ATL.22 Recently, constitutive activation of LIL-Stat was detected in AML
cells.7 AML cells have also been reported to spontaneously
express the IL1B gene.23 Moreover, our transient
transfection studies argue that LIL-Stat in ATL cells acts as a
transcriptional activator through binding to the LILRE in the
IL1B gene.
| |
Footnotes |
Submitted August 19, 1999; accepted December 10, 1999.
Reprints: Junichi Tsukada, First Department of Internal
Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555 Japan; e-mail; jtsukada{at}med.uoeh-u.ac.jp.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Abstract
Introduction