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(Received for publication, March 11, 1996, and in revised form, May 23, 1996)
From the Wake Forest University Medical Center, Bowman Gray School
of Medicine, Department of Medicine, Section on Infectious Diseases,
Winston-Salem, North Carolina 27157
ABSTRACT In human monocytes, interleukin 1 We have found that, in the human pro-monocytic cell line, THP-1, the
lipopolysaccharide-induced expression of interleukin 1 INTRODUCTION Septic shock is a lethal syndrome and the principle cause of death
in patients in intensive care units (1). A number of microbial
products, including bacterial lipopolysaccharide (endotoxin), cause
septic shock by inducing the expression of proinflammatory genes.
Phagocytic cells, monocytes and neutrophils, respond to endotoxin by
producing the potent immune and inflammatory mediator, interleukin 1 (IL-1)1 (for review, see Ref. 2). In these
cells, endotoxin-stimulated IL-1 A number of laboratories have demonstrated a role for protein-tyrosine
phosphorylation in intracellular signals initiated by endotoxin.
Endotoxin stimulation has been shown to rapidly increase tyrosine
phosphorylation of a number of proteins (9, 10), and protein-tyrosine
kinases (PTKs) appear to be linked to endotoxin signaling at a number
of levels, including through the activation of nonreceptor PTKs,
p56lyn, p58hck, and p59c-fgr (11),
as well as through a PTK-dependent transient activation of
the mitogen-activated protein kinase (MAPK or ERK) family (12, 13). In
addition, PTK inhibitors have been shown to be effective in preventing
endotoxin-induced cytokine production, both in vivo (14) and
in vitro (10, 15).
Recent data have indicated that PTK activity is not involved in the
endotoxin-mediated nuclear localization of NF Using the human pro-monocytic cell line, THP-1, we sought to determine
the role of PTKs in endotoxin-stimulated transcription activation.
Specifically, we tested the transcription competency of NF EXPERIMENTAL PROCEDURES THP-1 cells were maintained in RPMI 1640 (Life
Technologies, Inc.) with 10% fetal bovine serum (HyClone) as described
previously (3). Low passage number and log-phase cells were used for
all experiments.
THP-1 cells were
pretreated for 30 min with 30 µg/ml genistein (LC Laboratories)
before addition of endotoxin (1 µg/ml, or as indicated in the legends
to the figures, Escherichia coli lipopolysaccharide 0111:B4,
Sigma) for 1 to 3 h. Total RNA was isolated from
2 × 107 cells/condition using RNA STAT-60TM (TEL-TEST
B, Inc.) according to the manufacturer's instructions. After transfer
to nylon membranes, IL-1 THP-1 cells (1 × 107 cells/transfection) were transfected with plasmids
containing 6 repeats of the NF THP-1 cells (2 × 107
cells/condition) were pretreated with genistein (30 µg/ml) for 30 min
before stimulation with endotoxin (1 µg/ml) or PMA (10 ng/ml) for 30 min as indicated in the figures. Nuclear extracts were prepared and
assayed for DNA binding of transcription factors as described
previously (20). Oligonucleotide probes used in DNA binding assays were
prepared using an Applied Biosystems model 380B automated DNA
synthesizer and contained the following sequences: a consensus NF RESULTS Bacterial endotoxin activates monocytes through
mechanisms that are incompletely characterized; however, recent studies
have implicated PTKs in endotoxin signal transduction (9, 10, 11, 12, 13, 14, 15).
Endotoxin is a potent inducer of IL-1
Recent studies have shown that endotoxin-induced
NF
We further investigated the specificity of
PTK-mediated transcription in response to endotoxin using a CAT
reporter gene that is dependent on the transcription factor, AP-1.
Treatment of THP-1 cells with PTK inhibitors prior to endotoxin
stimulation did not affect DNA binding or inhibit CAT expression
mediated by AP-1. Endotoxin-mediated activation of AP-1 appears to be
enhanced in the absence of PTK activity (Fig. 3,
A and B). Furthermore, AP-1 transcription
activity in THP-1 cells appears to be negatively regulated by PTKs, as
protein kinase C-induced AP-1 transcription activity is also enhanced
in the absence of PTK activity (Fig. 3C). DNA binding by
AP-1 is not significantly affected by any of these treatments (Fig.
3D). These results demonstrate that PTK activity is not
required for the activation of transcription factors by endotoxin and
suggest a complex mechanism for activation of gene expression in
response to endotoxin. These studies further emphasize a potentially
critical role for NF
DISCUSSION It has been well established that many transcription factors are
modified in response to a variety of stimuli to achieve gene
activation/repression (for review, see Ref. 21). While the pattern of
transcription factor modification, most commonly protein
phosphorylation, has been relatively easily elucidated, the physiologic
mechanisms involved in transcription activation have only now begun
emerging. Transcription factor nuclear localization, DNA binding, and
interactions with the basic transcription machinery as well as with
other transcription factors are all potential regulatory targets in the
activation of gene expression by extracellular signals.
Non-receptor PTKs (11) and the MAPK/ERK family (12, 13) have been
implicated in the signal transduction pathway utilized by endotoxin.
Significantly, in vitro studies have shown that at least one
transcription factor, ATF-2, is directly phosphorylated by the p38
member of the MAPK/ERK family in response to endotoxin (22).
Phosphorylation of ATF-2 by p38 was mapped to the amino-terminal
activation domain at sites known to increase the transcriptional
activity of ATF-2. Subcellular localization of p38 showed cytoplasmic
and nuclear pools, establishing a spatial link between this kinase and
potential transcription factor targets within the nucleus. Specific
inhibitors of p38 MAPK/ERK have implicated this kinase in the signal
transduction pathway to increased expression of inflammatory cytokines
(23), and recent co-transfection studies have established a direct link
between p38 activation and tumor necrosis factor promoter activation
(24).
In the absence of genetic analyses, like gene ``knock-out'' or
``dominant negative'' mutants, signal transduction pathways are often
dissected through the use of protein kinase inhibitors. Many classes of
inhibitors have been utilized in numerous studies, yet the complex and
compensatory nature of intracellular signaling has made exact mapping
of these pathways elusive. In the studies we have presented, the
activation of single transcription factors were used as a measure of
intracellular signaling by endotoxin. We have been able to demonstrate
that NF We also observed enhanced transactivation by AP-1 in the absence of PTK
activity. Activation of AP-1 is known to involve JNK or SAPK, which are
functionally distinct members of the MAPK/ERK family (27). The
endotoxin signaling pathway can diverge at MKK4, the MAPK kinase
thought to be immediately upstream of JNK/SAPK and p38 kinases. Our
results show that endotoxin induction of junB mRNA
accumulation is unaffected by PTKs and suggest that endotoxin signals
through MKK4 may affect gene expression, in part by differential
activation/repression of transcription factors. The enhanced AP-1
transcription activation that we have observed may be due, in part, to
increased accumulation of the junB component of the AP-1
transcription complex. Alternatively, a number of parallel
intracellular signals may be integrated at the nucleus, ultimately
determining the potential for gene expression. Our assay system allows
us to measure the transactivation potential of individual transcription
factors, thus simplifying the integration of intracellular signals, and
may allow more precise mapping of signaling pathways to the
nucleus.
The salient feature of the MAPK/ERK family is the requirement for dual
phosphorylation on threonine and tyrosine residues for kinase activity.
The molecular targets for MAP/ERK activity include the
microtubule-associated protein 2, the S6 ribosomal kinase, and
transcription factors, such as c-Jun and ATF-2. The precise function of
MAP kinases in monocytes is not known, and many, if not all, of these
molecular targets may respond to endotoxin. We have shown that
endotoxin mediates gene expression, at least in part, through the
activation of transcription factors and that the transactivation
potential of a given transcription factor may be determined by
protein-tyrosine kinases activated by endotoxin. Whether this response
is altered by endotoxin as a direct result of MAPK/ERK activity is not
clear at this time. Tyrosine kinases are not required for
endotoxin-mediated signaling to the nucleus, as is evidenced by
endotoxin-mediated nuclear translocation of NF FOOTNOTES Acknowledgments Oligonucleotide synthesis was performed in
the DNA Synthesis Core Laboratory of the Cancer Center of Wake Forest
University, supported in part by National Institutes of Health Grant
CA-12197.
REFERENCES
Volume 271, Number 31,
Issue of August 2, 1996
pp. 18306-18309
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
and NF
B
Activation, but Not NFB Nuclear Translocation*
,
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
Acknowledgments
REFERENCES
protein
production and steady state mRNA levels are increased in response
to lipopolysaccharide, predominantly as a result of increased
transcription of the interleukin 1 gene. Expression of interleukin
1 and other cytokines, such as interleukin 6 and tumor necrosis
factor 
, has been shown to be dependent on the activation of the
transcription factor, NF
B. Since recent studies have shown that
lipopolysaccharide-induced tyrosine kinase activation is not required
for NFB nuclear translocation, we sought to determine whether NFB
translocated in the absence of tyrosine kinase activity was active in
stimulating transcription.
is dependent
on tyrosine kinase activation. Tyrosine kinases are not required for
lipopolysaccharide-mediated nuclear translocation of NFB. However,
in the absence of tyrosine kinase activity, the ability of NFB to
stimulate transcription is impaired. This inhibition of transcription
is specific for NFB; in the absence of tyrosine kinase activity,
AP-1-dependent transcription is enhanced. These results
suggest that, while lipopolysaccharide-induced expression of
inflammatory mediators requires tyrosine kinase activity, tyrosine
kinase activity is not obligatory for lipopolysaccharide signal
transduction.
production can be attributed to
rapid increases in transcription of the IL-1 gene, which occurs in
the absence of new protein synthesis (3, 4). Expression of IL-1 and
other cytokines, such as tumor necrosis factor , has been shown to
be dependent on the activation of the transcription factor, NFB
(5, 6, 7, 8).
B (16). Although
specific NFB family members may mediate transcription depending on
the inducer, cell type, and gene context (for review, see Ref. 17),
nuclear localization of NFB is generally paralleled by increases in
NFB-dependent transcription. While it is likely that
endotoxin signaling pathways other than those regulating NFB
activity are involved in the production of inflammatory mediators,
NFB is thought to play a central role in the transcription of
IL-1 gene (5, 6).
B
translocated to the nucleus in the absence of PTK activity. We found
that, similar to peripheral blood monocytes, endotoxin-induced IL-1
expression by THP-1 cells was dependent on PTK activity. In the absence
of PTK activity, endotoxin was unable to induce IL-1 mRNA or
activate NFB-dependent transcription, despite nuclear
translocation of NFB. These results show that NFB can be
regulated at two separate and distinct levels, nuclear translocation
and transcription activation. PTKs appear to play a critical role at
the level of transcription activation mediated by NFB. We further
show that, in the absence of PTK activity, endotoxin-mediated
activation of AP-1 is enhanced. These data indicate that PTK activity
is not obligatory for endotoxin signal transduction and suggest a
complex mechanism for signal transduction in the activation of
transcription factors by endotoxin. These studies provide further
evidence supporting a pivotal role for NFB in mediating the
expression of inflammatory mediators.
, tumor necrosis factor ,
junB, and glyceraldehyde-3-phosphate dehydrogenase mRNAs
were visualized by autoradiography as described previously (3).
B consensus binding site of the kappa
light chain immunoglobulin enhancer (pNH.dAN.6XKB.gfib.CAT, kindly
provided by Dr. E. O'Neill) or 3 repeats of the AP-1 consensus binding
site of the human collagenase gene (Col-TRE × 3/TK CAT, kindly
provided by Dr. P. Angel) linked to the CAT (chloramphenicol
acetyltransferase) reporter gene using DEAE-dextran as described by
Shirakawa and co-workers (18). After 18-20 h, cells were pretreated
with genistein (30 µg/ml) and then stimulated as indicated in the
figure legends with endotoxin (1 µg/ml) or PMA (10 ng/ml,
Sigma) for 6 h. CAT activity was measured in cell
lysates according to the method of Sleigh (19).
B
binding site derived from the kappa light chain immunoglobulin
enhancer, 5
-AATTCTCAACAGAGGGGACTTTCCGAG-3 and the
complementary strand; a consensus AP-1 binding site derived from the
human collagenase gene, 5-AATTCAACGTTGATGAGTCAGCCGGATCCG-3
and the complementary strand. The octamer-1 consensus binding site
derived from the immunoglobulin heavy chain enhancer contained
5-AACACCACCTGGGTAATTTGCATTTCTAAA-3 and the complementary
strand. Antibodies used in the supershift assays were obtained from
Santa Cruz Biotechnology.
expression in human monocytes
and in the pro-monocytic cell line, THP-1. To determine the role of
PTKs in the induction of IL-1 expression, THP-1 cells were
stimulated with endotoxin in the presence of inhibitors of PTKs. As
shown in Fig. 1, preincubation with the PTK inhibitor,
genistein, inhibited endotoxin-stimulated IL-1 mRNA
accumulation. Dose-response studies confirmed the inhibitory effects of
genistein at a variety of endotoxin concentrations. Similar results
were seen in human blood monocytes and with another PTK inhibitor,
herbimycin A (data not shown). Endotoxin-mediated tumor necrosis factor
mRNA accumulation is similarly inhibited by preincubation with
genistein. In contrast, endotoxin-stimulated junB mRNA
accumulation is unaffected by preincubation with protein-tyrosine
kinase inhibitors. These results indicated that PTKs can specifically
mediate endotoxin induction of IL-1 and allowed us to further
investigate the role of PTKs in the activation of transcription factors
by endotoxin in THP-1 cells.
Fig. 1.
Protein-tyrosine kinases mediate endotoxin
induction of IL-1. A, THP-1 cells were pretreated with
medium (M), genistein (G), or vehicle
(V, ethanol and dimethyl sulfoxide, each at 0.001% final
concentration) and stimulated with endotoxin (LPS, 1 µg/ml) as described under ``Experimental Procedures.'' Northern
blots of total RNA were hybridized with a nick-translated,
32P-labeled IL-1 cDNA probe (IL-1), tumor
necrosis cDNA probe (TNF), or junB
cDNA probe (Jun B) and visualized by autoradiography.
Northern blots were stripped and reprobed with a nick-translated,
32P-labeled glyceraldehyde-3-phosphate dehydrogenase
cDNA probe (GAPDH) as a control. B, THP-1
cells were pretreated with vehicle (+V, as described above)
or genistein (+G) and stimulated with increasing endotoxin
concentrations, 0.1 ng/ml, 1 ng/ml, 10 ng/ml, 100 ng/ml, and 1 µg/ml,
as described under ``Experimental Procedures.'' Northern blots were
hybridized with an IL-1 cDNA probe (IL-1B) or
glyceraldehyde phosphate dehydrogenase cDNA probe
(GAPDH) and visualized by autoradiography.
B
Activation
B nuclear localization is not dependent on PTK activation (16). We
directly tested the transcription competency of NFB translocated to
the nucleus in the absence of PTK activity. Using a CAT reporter gene
that is dependent only on NFB activation, we found that in the
absence of PTK activity, endotoxin was unable to activate
NFB-dependent transcription (Fig. 2,
A and B). Nuclear localization of NFB induced
by endotoxin in THP-1 cells was unaffected by the presence of PTK
inhibitors, both with respect to DNA binding (Fig. 2C) and
NFB subunit composition (Fig. 2D). These results suggest
that NFB can be regulated at two separate and distinct levels,
nuclear translocation and transcription activation. PTKs are apparently
involved in the regulation of NFB transcription activity.
Fig. 2.
Protein-tyrosine kinases mediate the
endotoxin induction of NFB activation. THP-1 cells were
transfected with a CAT reporter gene (pNH.dAN.6XKB.gfib.CAT) that is
dependent only on NFB activation. Transfected cells were pretreated
with medium, vehicle (ethanol and dimethyl sulfoxide, each at 0.001%
final concentration), or genistein and stimulated with endotoxin (+LPS)
as described under ``Experimental Procedures.'' The results
(expressed as -fold increase over 
LPS) of a single
representative experiment are shown in A. The averaged
result of three separate experiments is shown in B, where
the endotoxin-stimulated CAT activity in genistein-pretreated samples
are expressed as a percentage of the CAT activity after pretreatment
with vehicle alone (100%). DNA binding of NFB in nuclear extracts
of THP-1 cells was assessed by electrophoretic mobility shift assay and
a representative autoradiograph of three separate experiments is shown
in C. THP-1 cells were pretreated with vehicle (ethanol and
dimethyl sulfoxide, each at 0.001% final concentration) or genistein
and stimulated with endotoxin (+LPS) as described under
``Experimental Procedures.'' NF protein-DNA complexes as
visualized by autoradiography are indicated by the arrow.
EMSA supershift assays were performed by including antibodies to NFB
p50, NFB p65, c-Rel, and various combinations as indicated in
D. Position of the antibody-NFB-DNA complexes is
indicated (*).
B in mediating the expression of inflammatory
genes.
Fig. 3.
Protein-tyrosine kinases mediate endotoxin
induction of AP-1 activation. THP-1 cells were transfected with a
CAT reporter gene (Col-TRE × 3/TK CAT) that is dependent only on
AP-1 activation. Transfected cells were pretreated with medium, vehicle
(ethanol and dimethyl sulfoxide, each at 0.001% final concentration),
or genistein and stimulated with endotoxin (+LPS) as
described under ``Experimental Procedures.'' The results (expressed
as -fold increase over LPS) of a single representative
experiment are shown in A. The averaged result of two
separate experiments is shown in B, where the endotoxin
stimulated CAT activity in the genistein-pretreated sample is expressed
as a percentage of the CAT activity after pretreatment with vehicle
alone (100%). Protein kinase C stimulation of CAT activity in PMA
treated THP-1 cells is shown in C, where the averaged result
of 2 separate experiments of genistein-pretreated samples are expressed
as a percentage of the CAT activity after pretreatment with vehicle
alone (100%). DNA binding of AP-1 in nuclear extracts of THP-1 cells
was assessed by electrophoretic mobility shift assay, and a
representative autoradiograph of three separate experiments is shown in
D. THP-1 cells were pretreated with vehicle (ethanol and
dimethyl sulfoxide, each at 0.001% final concentration) or genistein
and stimulated with endotoxin (+LPS) or PMA as described
under ``Experimental Procedures.'' AP-1 protein-DNA complexes as
visualized by autoradiography are indicated by the arrow.
Octamer factor-1 (OCT) DNA binding was used as a
control.
B can be regulated not only at the level of nuclear
translocation (which has already been well characterized and reviewed
in Ref. 25), but more importantly, at the level of transcription
activation. Our results indicate that PTKs play an important role in
the regulation of the latter process. Recent studies have shown that
the transactivating domain of the p65 subunit of NFB interacts with
the TATA-binding protein component of the basic transcription machinery
(26). What role PTKs may play in this subsequent step in NFB
transactivation is not yet known.
B and enhanced AP-1
activation in the presence of PTK inhibitors. These results suggest a
complex mechanism for signal transduction in the activation of gene
expression by endotoxin. Our finding that NFB is inactive and that
IL-1 (and tumor necrosis factor ) is not expressed in the absence
of PTK activity provides further support for a model in which NFB
plays a critical role in mediating the expression of inflammatory
mediators.
Recipient of Individual Allocation IRG-198 from the American
Cancer Society. To whom correspondence should be addressed. Tel.:
910-716-9397; Fax: 910-716-7492.
1
The abbreviations used are: IL-1, interleukin 1;
NFB, nuclear factor B; PTK, protein-tyrosine kinase; MAPK,
mitogen-activated protein kinase; ERK, extracellular regulated kinase;
CAT, chloramphenicol acetyltransferase; PMA, phorbol 12-myristate
13-acetate; JNK, Jun kinase; SAPK, stress-activated protein kinase;
LPS, lipopolysaccharide.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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M. Bergmann, L. Hart, M. Lindsay, P. J. Barnes, and R. Newton Ikappa Balpha Degradation and Nuclear Factor-kappa B DNA Binding Are Insufficient for Interleukin-1beta and Tumor Necrosis Factor-alpha -induced kappa B-dependent Transcription. REQUIREMENT FOR AN ADDITIONAL ACTIVATION PATHWAY J. Biol. Chem., March 20, 1998; 273(12): 6607 - 6610. [Abstract] [Full Text] [PDF]
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T. S. Finco, J. K. Westwick, J. L. Norris, A. A. Beg, C. J. Der, and A. S. Baldwin Jr. Oncogenic Ha-Ras-induced Signaling Activates NF-kappa B Transcriptional Activity, Which Is Required for Cellular Transformation J. Biol. Chem., September 26, 1997; 272(39): 24113 - 24116. [Abstract] [Full Text] [PDF]
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C. M. Krejsa, S. G. Nadler, J. M. Esselstyn, T. J. Kavanagh, J. A. Ledbetter, and G. L. Schieven Role of Oxidative Stress in the Action of Vanadium Phosphotyrosine Phosphatase Inhibitors. REDOX INDEPENDENT ACTIVATION OF NF-kappa B J. Biol. Chem., April 25, 1997; 272(17): 11541 - 11549. [Abstract] [Full Text] [PDF]
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D. Wang, S. D. Westerheide, J. L. Hanson, and A. S. Baldwin Jr. Tumor Necrosis Factor alpha -induced Phosphorylation of RelA/p65 on Ser529 Is Controlled by Casein Kinase II J. Biol. Chem., October 13, 2000; 275(42): 32592 - 32597. [Abstract] [Full Text] [PDF]
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H. Uranishi, T. Tetsuka, M. Yamashita, K. Asamitsu, M. Shimizu, M. Itoh, and T. Okamoto Involvement of the Pro-oncoprotein TLS (Translocated in Liposarcoma) in Nuclear Factor-kappa B p65-mediated Transcription as a Coactivator J. Biol. Chem., April 13, 2001; 276(16): 13395 - 13401. [Abstract] [Full Text] [PDF]
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