(Circulation. 1999;100:1330-1337.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Inhibition of NF-
B Activation by Pyrrolidine Dithiocarbamate Prevents In Vivo Expression of Proinflammatory Genes
From the Department of Pharmacology, the University of Illinois College of Medicine, Chicago.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—The inability to inhibit multiple mediators of septic shock represents a major hurdle in the treatment of septic shock. In vivo inhibition of nuclear factor (NF)-
B activation, a transcription factor regulating
expression of many proinflammatory genes, could provide a useful
strategy for the treatment of septic shock.
Methods and Results—In rats challenged with
lipopolysaccharide (LPS) 8 mg/kg IV, we determined the time
course of NF-B activation and expression of multiple inflammatory
signals: tumor necrosis factor-
(TNF-),
cyclooxygenase-2 (COX-2),
cytokine-inducible neutrophil chemoattractant (CINC), and
intercellular adhesion molecule-1 (ICAM)-1. We studied the effects of
in vivo inhibition of NF-B activation using pyrrolidine
dithiocarbamate (PDTC) on the expression of these mediators. NF-B
activation preceded the induction of TNF-, COX-2, CINC, and ICAM-1
mRNAs. PDTC prevented the LPS-induced NF-B activation but did not
inhibit activation of the transcription factors AP-1, Sp-1, and CREB.
PDTC inhibited the LPS-induced expression of TNF-, COX-2, CINC, and
ICAM-1 mRNA and proteins and reduced the LPS-induced increases in
plasma TNF-, 6-keto-prostaglandin F1, and
CINC concentrations. Inhibition of expression of these mediators
prevented the increases in myeloperoxidase activity (a measure of
neutrophil sequestration) in the heart, lungs, and liver.
Conclusions—NF-B activation correlates with LPS-induced
expression of TNF-, COX-2, CINC, and ICAM-1 genes in vivo. PDTC
inhibits NF-B activation and expression of these proinflammatory
genes and their products. Thus, blocking NF-B activation may be
an effective strategy in the treatment of septic shock.
Key Words: shock • genes • nuclear factor • proteins • cell adhesion molecules
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The treatment of septic shock is complicated by the redundancy of mediators involved in its pathogenesis.1 2 3 4 5 Inhibition of actions of mediators can be compensated by the release of other mediators. Bacterial endotoxin triggers mediator release through the activation of multiple proinflammatory genes.1 2 3 4 5 Promoter deletion mutagenesis and reporter gene analysis in cultured cell lines have shown that the transcription factor nuclear factor (NF)-
B plays an essential role in transcriptional regulation
of these genes.6 7 8 NF-B is an appropriate target for
the treatment of septic shock because NF-B–activated gene
products play important roles in the pathogenesis of septic shock
and multiple organ failure.2 3 4 5 In the present
study, we determined the time course of NF-B activation by
lipopolysaccharide (LPS) in relation to the expression of tumor
necrosis factor (TNF)-, cyclooxygenase (COX)-2,
intercellular adhesion molecule (ICAM)-1, and
cytokine-induced neutrophil chemoattractant (CINC). We
studied (1) the selectivity of pyrrolidine dithiocarbamate (PDTC) as an
in vivo inhibitor of NF-B activation and (2) the effects
of PDTC on LPS-induced expression of these proinflammatory gene
products and the resultant tissue neutrophil sequestration in
multiple organs. |
Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Animal Protocols
Male Sprague-Dawley rats (350 to 400 g; Charles River, Wilmington, Mass) were randomly divided into experimental groups. All procedures were approved by the Institutional Animal Care Committee. Animals in the control and LPS groups were injected with either saline 1 mL/kg IV or Salmonella enteritidis LPS (Sigma) 8 mg/kg in saline IV. Rats in the LPS plus PDTC groups were injected with 50, 100, or 200 mg/kg PDTC IP 1 hour before administration of LPS; animals in the PDTC alone group were treated with PDTC 200 mg/kg IP for an equivalent period.
The animals were killed by exsanguination, and heart, lungs, and liver
were collected at 0.25, 0.5, 1, 2, or 4 hours after LPS challenge.
Animals in the PDTC alone group were killed at 2 or 5 hours. Blood
samples (1 mL) were collected at 4 hours after LPS challenge or 5 hours
after PDTC administration for determination of plasma TNF-,
6-keto-prostaglandin F1
(PGF1), CINC, and soluble ICAM-1
concentrations. Tissues were snap-frozen in liquid nitrogen and kept at
-70°C.
Nuclear Protein Extract and Electrophoretic Mobility Shift
Assay
Nuclear protein was extracted and quantified as
described.9 NF-B, activating protein-1 (AP-1), AP-2,
cAMP response element–binding protein (CREB), and promoter selective
transcription factor (Sp-1) consensus oligonucleotide
probes (for sequences, see Table 1
) were end-labeled with
[
-32P]ATP (Amersham). Electrophoretic
mobility shift assay (EMSA) competition experiments and supershift
assays were performed as described.9
MgCl2 5 mmol/L was added to binding buffer
for detection of AP-1.9
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Northern Blot Analysis
Rat cDNA probes for COX-2 (381 bp), CINC (207 bp), and ICAM-1
(384 bp) were amplified in a standard reverse-transcription polymerase
chain reaction procedure using RNA from lungs obtained from
LPS-treated rats and designed primers corresponding to the published
rat COX-2,10 CINC,11 and
ICAM-112 cDNA sequences. The authenticities of the
polymerase chain reaction products were confirmed by dideoxy chain
termination sequencing. Rat TNF- cDNA probe was provided by Dr E.
Benveniste (University of Alabama at Birmingham).13 RNA
isolation, Northern blotting, and hybridization were carried out as
described.9 Each hybridization was followed by film
exposure and stripping down of the previous probe before hybridization
with other probes.
Protein Extraction and Western Blot Analysis
Heart, lungs, and liver were homogenized in 10
volumes of ice-cold protein-extracting buffer containing
0.5 mmol/L EDTA, 0.5 mmol/L EGTA, 10 mg/mL leupeptin,
0.1 mg/mL phenylmethylsulfonylfluoride, and 1 mmol/L
pepstatin. The homogenate was centrifuged at
17 500g for 15 minutes, and the resulting supernatant was
collected as the cytosolic fraction. The pellet was resuspended in
extracting buffer containing 0.1% triton X-100,
homogenized, and centrifuged at 17 500g
again for 30 minutes. The second supernatant was centrifuged at
90 000g for 60 minutes. The resulting pellet was taken to
be the membrane fraction. Protein concentration was determined by use
of a bicinchoninic acid assay kit with BSA as the standard
(Pierce).
Protein (50 µg/lane) was separated on 7.5% (for COX-2 and ICAM-1) or
15% (for CINC and TNF-) SDS-polyacrylamide slab gel under
denaturing conditions and was electroblotted to nitrocellulose membrane
(BioRad). BioRad protein molecular weight markers were used as
standards. After incubation in 5% dry milk in PBS containing 0.05%
Tween-20 (PBST) at room temperature (RT) for 2 hours, the
membrane was immunoblotted to the following antibodies
(Abs) at RT for 1 hour in separate experiments: anti–rat COX-2
monoclonal Ab (Transduction Laboratory), anti–rat TNF- polyclonal
Ab (Santa Cruz Biotechnology), anti–rat ICAM-1 monoclonal Ab
(PharMingen), and anti-CINC polyclonal Ab (provided by Dr Zagorski,
National Institutes of Health). The secondary Abs were horseradish
peroxidase–conjugated goat anti-mouse, monkey anti-goat, or horse
anti-rabbit Abs. Peroxidase labeling was detected with the ECL Western
blotting detection system (Amersham).
Plasma TNF-, 6-keto-PGF1, CINC, and Soluble
ICAM-1 Measurements
Plasma TNF- concentration was determined by ELISA kit
(Genzyme). Plasma 6-keto-PGF1 concentration
was determined by use of a 6-keto-PGF1 enzyme
immunoassay kit (Cayman Chemical). Plasma concentration of CINC was
quantified by ELISA.14 To determine plasma soluble ICAM-1
level, 5 µg plasma protein in 50 mmol/L bicarbonate buffer (pH
9.5) was added to microtitration plates (Dynatech) overnight at 4°C.
The wells were washed 4 times with PBST, blocked with 5% dry milk in
PBST at RT for 2 hours, and incubated with anti–rat ICAM-1 monoclonal
Ab at RT for a further 2 hours. After 4 washings with PBST, horseradish
peroxidase–conjugated anti-mouse IgG was added. Color was developed by
addition of TMB peroxidase substrate mixture (Sigma) and read in a
microplate reader at a wavelength of 450 nm after addition of stopping
buffer.
Measurement of Tissue Myeloperoxidase Activity
We used tissue myeloperoxidase (MPO) activity as the index of
tissue neutrophil uptake. MPO was extracted from heart, lungs, and
liver.15 MPO activity in supernatant was measured from the
optical density (at 460 nm) changes resulting from decomposition of
H2O2 in the presence of
o-dianisidine.15
Data Analysis
Bands for TNF-, COX-2, CINC, ICAM-1, and GAPDH on Northern
blot autoradiograms and Western blots were quantified
by a laser densitometer (Howtek) linked to a computer analysis
system (PDI). The relative TNF-, COX-2, CINC, and ICAM-1 RNA
concentrations were expressed as percentage of corresponding GAPDH
bands. Data are presented as mean±SEM. Results were
analyzed with Kruskal-Wallis rank test followed by Mann-Whitney
U test for stepwise comparison.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Time Course of NF-
B Activation and Inflammatory Gene
ExpressionFigure 1
shows the time course of
LPS-induced NF-B/DNA–binding activity and its relationship to
TNF-, COX-2, CINC, and ICAM-1 mRNA expression in lungs.
NF-B/DNA–binding activity was detectable at low levels in control
lungs, increased slightly at 5 or 10 minutes after LPS challenge, and
increased markedly after treatment with LPS for 
15 minutes (Figure 1). The specificity of NF-B/DNA–binding complex was
confirmed by complete displacement of NF-B/DNA complex in the
presence of 50-fold molar excess unlabeled NF-B probe (Figure 2A). In contrast, 50-fold molar excess of
unlabeled AP-2 oligo probe had no effect on DNA-binding complex (Figure 2A). A slower or faster migrating band was seen in some assays,
but this was not induced by LPS. The composition of
LPS-activated NF-B complex consisted predominantly of p50
and p65 subunits of the NF-B protein family, as determined in
supershift assays (Figure 2B).
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We determined the time course of LPS-induced TNF-, COX-2, CINC, and
ICAM-1 mRNA expression in the same tissues as used for EMSA. We
observed different kinetics in the expression of these genes (Figure 1
). CINC mRNA was absent, but TNF- and COX-2 mRNAs were
detected at low levels in control lungs; ICAM-1 mRNA was expressed at
high levels in control lungs. LPS challenge induced expression of
TNF-, COX-2, and CINC mRNA transcripts and upregulated ICAM-1 mRNA
in a time-dependent manner. The threshold times for LPS-induced mRNA
expression were 15 to 30, 30 to 60, and 120 minutes after LPS for
TNF- and ICAM-1, CINC, and COX-2, respectively (Figure 1). In
all cases, this was preceded by NF-B activation, which showed a
threshold time of 10 to 15 minutes (Figure 1). Increases in
TNF- and ICAM-1 mRNA expression were maximal at 1 to 2 hours after
LPS, whereas CINC and COX-2 mRNA expression peaked at 4 hours (Figure 1). This was also preceded by NF-B activation (which peaked
at 30 minutes after LPS) (Figure 1).
PDTC Inhibits In Vivo NF-B Activation
We compared the effects of PDTC on activation of NF-B as well
as the other transcription factors AP-1, AP-2, CREB, and Sp-1 in lungs.
PDTC suppressed LPS-induced NF-B/DNA–binding activity in a
dose-dependent manner (Figure 3, lane 1).
PDTC did not inhibit LPS-induced AP-1/DNA–binding activity (Figure 3, lane 2); a higher dose of PDTC (200 mg/kg) potentiated the
LPS-induced AP-1/DNA–binding activity. PDTC alone at 200 mg/kg
increased AP-1/DNA–binding activity (Figure 3, lane 2). PDTC
also had no effect on the LPS-induced downregulation of
AP-2/DNA–binding activity (Figure 3, lane 3) and upregulation
of CREB/DNA–binding activity (Figure 3, lane 4).
Sp-1/DNA–binding activity was detected at a high level in control
nuclear extracts, but it was not affected by either LPS or PDTC (Figure 3, lane 5).
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PDTC Inhibits In Vivo Expression of Inflammatory Genes
As shown in Figures 4, 5, and 6,
2.6-kb TNF-, 4.4-kb COX-2, and 0.93-kb CINC mRNA transcripts were
absent or negligible in control hearts and lungs (Figures 5 and 6), and 2.6-kb ICAM-1 mRNA transcript was absent in control
hearts (Figure 5D) but was detected at high levels in control
lungs (Figure 6D). Increases in mRNA levels of these genes after
LPS challenge were prevented by PDTC treatment, with PDTC alone having
no independent effect (Figures 4, 5, and 6). We
quantified TNF-, CINC, COX-2, and ICAM-1 bands by densitometry and
normalized these bands to their corresponding GAPDH bands. Neither LPS
nor PDTC had a significant effect on GAPDH mRNA transcription (Figure 4). However, LPS in all cases increased TNF-/GAPDH,
COX-2/GAPDH, CINC/GAPDH, and ICAM-1/GAPDH ratios in both heart (Figure 5) and lungs (Figure 6). PDTC suppressed LPS-induced
increase in TNF-/GAPDH and COX-2/GAPDH ratios in a dose-related
manner (Figures 5A, 5B, 6A, and 6B). Reductions in
LPS-induced CINC/GAPDH and ICAM-1/GAPDH ratios were also dose-related
in both organs, except at a PDTC concentration of 200 mg/kg (Figures 5C, 5D, 6C, and 6D).
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PDTC Inhibits LPS-Induced TNF-, COX-2, CINC, and ICAM-1
Protein Expression
We compared TNF-, COX-2, CINC, and ICAM-1 protein levels in
tissue homogenates of heart, lungs, and liver from control
rats, rats challenged with LPS for 4 hours, rats pretreated with PDTC
for 1 hour before challenge with LPS for 4 hours, and rats treated with
PDTC alone. Figure 7 shows Western blots
illustrating inhibition by PDTC of LPS-induced upregulation of these
proteins. Western blot bands were quantified by densitometry (data are
presented as optical density units in Table 2). The 6.5-kD CINC, 14-kD TNF-, 69-kD
COX-2, and 70-kD ICAM-1 proteins were detectable in control
homogenates but were markedly increased by LPS challenge in
the 3 organs (Figure 7; Table 2). Pretreatment with 50,
100, and 200 mg/kg of PDTC suppressed the expression of these proteins,
although the response was variable (Figure 7; Table 2). A 95-kD ICAM-1 protein was also detected in the heart, which
was increased by LPS and prevented by PDTC in a fashion similar to that
seen with the 70-kD ICAM-1 protein. The 95-kD ICAM-1 protein band was
not seen in lung and liver homogenates, suggesting an
organ-specific glycosylation of ICAM-1. Suppression by PDTC of
LPS-induced expression of these proteins did not show clear
dose-dependency, except with COX-2 and ICAM-1 in lung
homogenates and TNF- in heart homogenates
(Figures 7; Table 2). Maximal inhibition of CINC
expression in heart and lungs and ICAM-1 expression in heart (Table 2) was observed at a PDTC concentration of 100 mg/kg. This
was the same concentration at which PDTC maximally suppressed
LPS-induced CINC and ICAM-1 mRNA expression in heart and lungs (Figures 5C, 5D, 6C, and 6D). A similar pattern of inhibition of
LPS-induced plasma CINC concentration (Figure 8C) and tissue MPO activities in heart,
lungs, and liver was also observed (Table 3).
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PDTC Inhibits Increase in Plasma Concentrations of TNF-,
6-keto-PGF1, and CINC
We determined the effects of PDTC on plasma TNF-,
6-keto-PGF1 (an indicator of COX-2 activity),
CINC, and soluble ICAM-1 concentration. Control animals showed little
plasma CINC, moderate concentrations of
6-keto-PGF1 and TNF-, and a high
concentration of soluble ICAM-1 (Figure 8). In LPS-challenged
animals, plasma TNF-, 6-keto-PGF1, CINC,
and soluble ICAM-1 concentrations increased by 8-, 4-, 18-, and 2-fold,
respectively (Figure 8). Pretreatment of LPS-challenged animals
with PDTC at concentrations of 50, 100, and 200 mg/kg reduced the
LPS-induced plasma TNF- levels by 58%, 76%, and 56%; plasma
6-keto-PGF1 levels by 58%, 51%, and 57%;
and plasma CINC levels by 62%, 78%, and 48%, respectively (Figure 8). PDTC had no effect on LPS-induced elevation of plasma
soluble ICAM-1 concentration (Figure 8D), although it
significantly inhibited the elevation in membrane-bound ICAM-1
concentration induced by LPS in heart, lungs, and liver (data not
shown). PDTC alone had no effects on plasma levels of these mediators
(Figure 8).
PDTC Reduces Neutrophil Sequestration
MPO activity (an index of neutrophil sequestration) increased
markedly in 3 organs 4 hours after LPS challenge (Table 3). PDTC
reduced the LPS-induced MPO activity in all organs studied. Maximal
inhibition of LPS-induced MPO activity was observed at a PDTC
concentration of 100 mg/kg, which correlated with inhibition of
LPS-induced CINC and ICAM-1 expression at this concentration (Figures 5C, 5D, 6C, 6D, and 8C and Table 3).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we determined (1) the in vivo relationship between NF-
B activation and expression of inflammatory
genes, (2) the in vivo selectivity of PDTC in inhibiting NF-B
activation, and (3) the effects of inhibiting NF-B activation by use
of PDTC on inflammatory genes and their products in multiple
organs. We studied the expression of TNF-, COX-2, ICAM-1, and CINC
because of their critical roles in the endotoxin-induced inflammatory
response.3 16 17 18 19 We demonstrated that LPS-induced NF-B
activation in vivo preceded the transcription of TNF-, COX-2, CINC,
and ICAM-1 genes. Pretreatment of rats with 50, 100, and 200 mg/kg of
PDTC suppressed LPS-induced NF-B/DNA–binding activity but not
AP-1–binding activity. PDTC also had no effect on DNA-binding
activities of the other transcription factors AP-2, CREB, and Sp-1,
indicating the relative selectivity of PDTC. We found that PDTC
inhibited TNF-, COX-2, CINC, and ICAM-1 mRNA and protein expression
and the increases in plasma TNF-,
6-keto-PGF1, and CINC concentrations induced
by LPS. PDTC also reduced LPS-induced tissue MPO activities in heart,
lungs, and liver, consistent with inhibition of neutrophil
sequestration in these organs. Because PDTC prevented the in vivo
NF-B activation induced by LPS and expression of TNF-, COX-2,
CINC, and ICAM-1, the results suggests a linkage between NF-B
activation and the expression of these genes.
A central feature of the pathophysiology of septic shock is that
bacterial endotoxins trigger release of multiple
cytokines.3 4 5 Although these cytokines
are required for the host-defense response, dysregulation of their
production can lead to refractory hypotension,
cardiovascular hyporeactivity, disseminated
intravascular coagulation, and multiple organ failure.1 2 3 4 5
Because septic shock involves multiple mediators, often with
overlapping functions, therapeutic strategies inhibiting actions of 1
mediators have not been effective. NF-B plays a critical role in the
transcriptional activation of multiple genes6 7 8 that
contribute to the development of septic shock and multiorgan failure.
NF-B/DNA–binding activity was increased in circulating monocytes
from septic shock patients.20 Inhibition of NF-B
activation prevented LPS- and cytokine-induced cell
activation and inflammatory gene expression in cultured
endothelial cells.21 22 We showed in a
previous study that inhibition of NF-B activation prevented
LPS-induced iNOS mRNA, iNOS activity, and systemic hypotension in a rat
model.9 Others have reported that inhibition of NF-B
activation reduced CINC mRNA expression and neutrophil infiltration in
lungs.23 In the present study, we showed that PDTC
prevents NF-B activation by a mechanism that involves inhibition of
I-B degradation24 and thereby prevents the expression
of inflammatory genes as well as neutrophil sequestration in multiple
organs. Because these results suggest an important functional role of
NF-B activation, interventions aimed at inhibiting NF-B
activation may provide effective strategies for treatment of septic
shock.
PDTC at 200 mg/kg, surprisingly, caused less inhibition of LPS-induced
expression of CINC and ICAM-1 mRNA than 100 mg/kg PDTC, although the
higher concentration produced greater inhibition of NF-B activation.
This dissociation between inhibition of NF-B activation and ICAM-1
mRNA expression may be explained by involvement of AP-1 in mediating
the response.8 17 25 PDTC 200 mg/kg was shown to
potentiate LPS-induced AP-1/DNA–binding activity (Figure 3, lane 2). Thus, it is likely that 200 mg/kg PDTC inhibited the
NF-B–mediated ICAM-1 mRNA expression but augmented AP-1–mediated
transcription of the ICAM-1 gene; the inhibitory effect of
PDTC mediated through NF-B inhibition was consequently offset by the
AP-1–mediated stimulatory effect.
Schreck et al26 showed that PDTC inhibited the LPS-,
TNF-–, and PMA-induced NF-B activation but had no effect on
activation of the transcription factors AP-1, CREB, Sp-1, and
octamer-binding proteins in several cell lines. Kawai et
al25 reported that PDTC suppressed IL-1–induced
NF-B and ICAM-1 promoter/CAT activities in a human fibroblast cell
line. The inhibitory effect of PDTC on ICAM-1 promoter/CAT
activity was abolished by deletion or mutation of the NF-B site on
the ICAM-1 promoter. Others have shown that PDTC inhibited expression
of NF-B–dependent genes in several cell types.21 25 27
We demonstrated in vivo that PDTC suppressed the LPS-induced activation
of NF-B by a mechanism that prevents degradation of
I-B.24 In contrast, PDTC had no effect on DNA-binding
activities of the transcription factors AP-1, AP-2, CREB, and Sp-1,
suggesting that PDTC is a relatively selective NF-B
inhibitor.
We have shown that in vivo activation of NF-B precedes TNF-,
COX-2, CINC, and ICAM-1 mRNA expression. Pretreatment of rats with PDTC
suppressed LPS-induced NF-B activation and prevented expression of
TNF-, COX-2, CINC, and ICAM-1 mRNA and their products as well as
neutrophil sequestration in heart, lungs, and liver. These results
suggest that NF-B activation mediates the expression of multiple
inflammatory genes and neutrophil sequestration in vivo.
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Acknowledgments |
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We would like to thank Dr J. Zagorski at the National Institutes of Health for providing anti-CINC antibody and Dr E.N. Benveniste at the University of Alabama at Birmingham for providing rat TNF-
cDNA probe. This work was supported by NHLBI grant HL-46350 (to
Dr Malik) and AHA grant 9650733N (to Dr Liu). |
Footnotes |
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Reprint requests to Asrar B. Malik, PhD, Professor and Head, the University of Illinois, Department of Pharmacology (M/C 868), 835 S Wolcott Ave, Chicago, IL 60612.
Received February 9, 1999; revision received April 28, 1999; accepted May 19, 1999.
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