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B in Different Cell Types Through Reactive Oxygen Intermediates
Cytokine Research Section Departments of
*
Molecular Oncology and
Bioimmunotherapy. University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B, we investigated the
effect of MAC on this nuclear transcription factor in cells of
macrophage and nonmacrophage lineage. We demonstrate that both high and
low virulence strains of MAC potently and rapidly activated NF-B. In
supershift assays, using specific Abs against the NF-B subunits, we
identified a p50/p65 heterodimer that was formed within 5 min after
incubation with the bacterium too rapidly for cytokines to be involved
in the activation. This activation was instead mediated through the
generation of reactive oxygen intermediates, inasmuch as preincubation
of cells with a variety of antioxidants inhibited NF-B activation.
Likewise, the transfection of cells with Mn-superoxide dismutase
blocked the NF-B activation induced by the bacterium. These data
suggest that NF-B activation is a consequence of interaction of host
cells with the bacterium and that the interaction may play a pivotal
role in the pathogenesis of the disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Given the drug resistance of the organism and the debilitated state of
most HIV-infected people, designing effective agents likely requires a
thorough understanding of the mechanism of host response to infection.
The production of immunomodulatory cytokines and activation of kinases
and transcription factors are the essential components of this host
response. Many of the targets of HIV-1 and MAC within the immune system
are identical, and these targets in turn produce various cytokines that
contribute to the host defense against infectious agents. One of the
keys to the control of cytokine production is the nuclear transcription
factor NF-B. Cytokines play an essential role in, among other
activities, the host immune response to microbial pathogens, including
bacteria, protozoa, fungi, chlamydia, and viruses. This response is
typically mediated by NF-B (7, 8, 9, 10, 11, 12, 13, 14, 15, 16).
NF-B is a dimeric ubiquitous transcription factor whose activity is
tightly regulated by cytokines and other external stimuli (17, 18).
Under most situations, NF-B is retained in the cytoplasm in latent
form as a heterotrimeric complex consisting of p50 (NF-B1), p65
(RelA) subunits, and an inhibitor, IB. The activation of NF-B
requires sequential phosphorylation, multiubiquitination, and
degradation of IB, with consequent exposure of the nuclear
localization signal in NF-B molecule (19, 20). The genes regulated
by this transcription factor encode proteins involved in rapid response
to pathogens or stress, including the acute-phase proteins, cytokines,
and cellular adhesion molecules (21). The role of the secretory
products, exotoxin, outer membrane components, invasive factor, and
virulence genes leading to the activation of NF-B have also been
documented.
The present study was undertaken to determine the effect of MAC on
NF-B activation in cells of both macrophage and nonmacrophage
origin. We demonstrate that the interaction of the host cells with MAC
causes NF-B activation. MAC did not activate NF-B in cells
transfected with MnSOD and in cells pretreated with antioxidants,
indicating the critical role of reactive oxygen intermediates (ROI) in
intracellular signaling.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Bacteria-derived purified human recombinant TNF was provided by
Genentech (South San Francisco, CA). LPS, pyrrolidine dithiocarbamate
(PDTC), 3-tert-butyl-4-hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), mannitol, N-acetylcysteine (NAC),
glutathione (GSH), cytochalasin B, and polymyxin B were purchased from
Sigma (St. Louis, MO). [
-32P]ATP was purchased from
ICN Pharmaceutical (Costa Mesa, CA), polynucleotide kinase from New
England Biolabs (Beverly, MA), and poly(dI:dC) from Pharmacia Biotech
(Almeda, CA).
Bacteria
The culture conditions of the wild-type MAC strain 101 (serovar 1), a patient isolate, have been described (22). The characterstics of bacteria were altered by passage in beige mice. The new colony morphotype was isolated and evaluated for the virulence in mice.
Cell culture, treatments, and infection
The cells used in this study included ML-1a, a human myelomonoblastic leukemia cell line kindly provided by Dr. Ken Takada (Showa University, Showa, Japan); U937, a human histiocytic lymphoma line; and acute T cell leukemia cell line Jurkat, were obtained from American Type Culture Collection (ATCC, Manassas, VA). Normal human diploid fibroblast (FS) cells were kindly provided by Dr. James Smith of Baylor College of Medicine (Houston, TX). All cells were grown in RPMI 1640 medium (Life Technologies, Grand Island, NY) supplemented with 10% FBS (Life Technologies), 2 mM glutamine, and antibiotics at 37°C in an atmosphere of 5% CO2 in air. Following infection for the stipulated time, the cells were washed in PBS containing gentamicin (50 µg/ml) to remove free bacteria and to prevent further interaction.
Human MCF-7 cells stably transfected with the expression vector pHßApr-1 carrying a human MnSOD cDNA insert was generously provided by Dr. Larry W. Oberley (University of Iowa, Iowa City, Iowa). The details of the construct have been described elsewhere (23). MCF-7 cells transfected only with the vector served as control (neo).
To examine the effect of various antioxidants, cells were pretreated with 25 µM PDTC, 50 mM mannitol, 10 µg/ml BHT, 10 µg/ml BHA, 2 mM GSH, and 25 µg/ml NAC for 1 h and then infected with MAC. Other pretreatments included 10 µg/ml polymyxin B for 30 min and 2 mM cytochalasin B for 15 min.
Antibodies
The polyclonal Abs used were as follows: anti-p65, against
the epitope corresponding to amino acids mapping within the amino
terminal domain of human NF-B p65; anti-p50, against a peptide
15 amino acids long mapping at the nuclear localization signal region
of NF-B p50 ; anti-IB-
, against amino acids 297–317
mapping at the carboxyl terminus of IB-/MAD-3 of human origin;
anti-IB-ß (amino acid 339–358) and
anti-c-rel, against the epitope corresponding to
300 amino acids mapping within the amino terminus of human
c-rel p75. These Abs were obtained from Santa Cruz
Biotechnology (Santa Cruz, CA).
Electrophoretic mobility shift assays (EMSA) and Ab supershifts
The details of the preparation of nuclear extracts and the assay
procedure have been described elsewhere (24, 25). Nuclear extracts were
either used immediately or stored at -70°C. Typically, 4 to 6 µg
protein was used per assay. The protein content of the extract was
measured by the method of Bradford (26). EMSAs were performed by
incubating nuclear extract with 32P-end-labeled 45-mer
double-stranded NF-B oligonucleotide from the HIV terminal repeat
5'-TTGTTACAAGGGACTTTCCGCT
GGGGACTTTCCAGGGAGGCGTGG-3'. A double-stranded mutated
oligonucleotide,
5'-TTGTTACAACTCACTTTCCGCTGCTCACTTTCCAGGGAGGCGTGG-3',
was used to examine the specificity of binding of NF-B to the DNA.
The specificity of binding was also examined by competition with the
unlabeled oligonucleotide. For supershift assays, Abs against p50, p65,
and c-rel subunits of NF-B were used as described (27).
Visualization and quantitation of radioactive bands were conducted by
PhosphorImager (Molecular Dynamics, Sunnyvale, CA) using Image
Quant software (National Institutes of Health, Bethesda, MD).
Determination of IB by Western blot
Western blot assays of IB- and IB-ß were generally
conducted with 25 to 30 µg of cytoplasmic extracts. The proteins were
resolved by SDS-PAGE and electrophoretically transferred to
nitrocellulose membranes. The membranes were blocked with PBS with
0.5% Tween 20 (PBST) containing 5% fat-free milk and then exposed to
either IB- (1 to 3000 dilution) or IB-ß (1 to
1000 dilution) Abs. The membranes were washed with PBST and treated
with secondary Ab conjugated to horse radish peroxidase. The Ag-Ab
reaction was visualized by an enhanced chemiluminescence (ECL) assay
using Amersham (Arlington Heights, IL) ECL reagents and exposure
to film.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B in different cell types
Because the host immune response is dependent on the activation of
the nuclear transcription factor NF-B, we investigated the effect of
MAC on this nuclear factor in cells of macrophage and nonmacrophage
lineage. Incubation of cells from a macrophage-like cell line, U937,
with different titers of MAC for 1 h, activated NF-B (Fig. 1
A). NF-B was also
activated in Jurkat (T) cells exposed to the mycobacterium (Fig. 1B) but not in FS cells (Fig. 1C). In U937 cells,
activation was dependent on the concentration of mycobacteria beginning
at dose of 1 x 104 bacteria, which induced 2.5- to
5.3-fold NF-B-DNA binding activity. NF-B activation was greater
in U937 than in Jurkat cells. The response in Jurkat cells, however,
was by and large uniform, since further increases in the nuclear
NF-B-DNA complex were not observed with increasing doses of
bacteria.
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B activation, U-937 and ML-1a cells
were exposed to MAC for different times and then analyzed by EMSA. As
shown in Figure 2, persistent activation
of NF-B was seen in the two myeloid cell types. In U937, the
DNA-binding activity gradually increased, reached its peak by 60 min,
and remained stabilized for up to 360 min (Fig. 2A). In
ML-1a cells, however, maximum NF-B activation could be seen within 5
min and remained steady for up to 360 min (Fig. 2C).
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B- undergoes proteolysis in response to
such diverse stimuli as bacterial endotoxin, cytokines, or phorbol
esters. Immunoblot analysis of cytoplasmic extracts from MAC-infected
U937 cells showed a maximum decrease in the levels of IB- by 30
min and then an increase until it reached the basal level (Fig. 2
B). It is known that the decrease of IB- is due to
degradation and the increase to NF-B-dependent resynthesis.
The activation of NF-B by LPS requires the degradation of IB-ß.
Thus, we also examined the cytoplasmic levels of IB-ß after
treatment of U-937 cells with the mycobacterium for different times.
Approximately 57% decrease in the levels of IB-ß occurred at 180
min following MAC infection (Fig. 2B). Thus, the degradation
of IB- by MAC occurs at a rate faster than that of IB-ß.
We also studied the effect of MAC on the activation of the transcription factors, AP-1 and Oct-1. Mycobacterial infection of U937 cells did not modulate the activity of either transcription factor (data not shown).
MAC-induced NF-B activation is reversible and composed of p50
and p65 subunits of NF-B but not c-rel
To estimate the stability of the interaction of NF-B protein
with the B DNA in the nucleus, we preexposed cells for 60 min to
MAC, washed the cells to remove MAC, and incubated them in
bacteria-free medium for different times. Nuclear extracts from these
cells were analyzed for NF-B-DNA complex at regular intervals by
EMSA. In a parallel experiment, U937 cells were continuously incubated
with MAC for comparative analysis. Figure 3A shows that the nuclear
NF-B-DNA-binding activity was undetectable by 3 h after
withdrawal of MAC but persisted if incubation was not interrupted.
These results indicate that the formation of NF-B-DNA complex
induced by the mycobacterium is transient.
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B-binding complex, we
employed Abs against the NF-B subunits for the supershift assays.
The nuclear extracts from MAC-treated U937 cells were incubated with
specific polyclonal Abs to p65 or p50 or c-rel before
addition of radiolabeled B oligonucleotide. As shown in Figure 3B, the p65 and p50 Abs, but not the c-rel Ab,
reacted with a component of the B complex to produce a slow
migrating complex. These results suggest that both p65 and p50
constitute the MAC-activated NF-B-DNA complex.
NF-B activation is independent of virulence and viability of MAC
To analyze the relationship of NF-B activation to virulence of
the organism, U937 cells were incubated with different doses of either
low or high virulent strains of mycobacterium. As shown in Figure 4, the ability of MAC to activate NF-B
was independent of its virulence. A dose-dependent increase in
NF-B-DNA-binding activity was seen in both low and high virulent
strains of MAC.
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B activation.
For this, U-937 cells were treated with mycobacteria that had been
heated to 100°C temperature for 30 min. As shown in Figure 5A, both live and heat-killed
MAC activated NF-B. The response was, however, stronger and
detectable earlier with live bacteria. The cytoplasmic degradation of
IB- could be noted in 15 min in cells exposed to live
mycobacteria (Fig. 5B) but not until 60 min in heat-killed
cells. These results suggest that the viability of mycobacteria,
although not essential, does contribute to the overall NF-B
activation and IB- degradation.
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B activation
Bacterial surface structures like LPS and lipoarabinomannan have
been demonstrated to activate NF-B (28, 29, 30, 31). Polymyxin B (PB) has
been shown to bind LPS and abrogate its effect. The latter transduces
its signal through the CD14 receptor. To determine whether the NF-B
activated by MAC was instead due to LPS, we incubated the mycobacterium
for 30 min with PB (10 µg/ml) and then with U937 cells. As Figure 6A shows, PB by itself did not
activate NF-B; preincubation of Salmonella-derived LPS
with PB for 15 min abrogated the ability of LPS to activate NF-B.
Pretreatment of MAC with PB, however, had no effect on the NF-B
activation induced by the mycobacterium. In addition, PB also had no
effect on TNF-induced NF-B activation. Thus, overall these results
demonstrate that the effect of the mycobacterium was not due to LPS.
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B is independent of TNF release
To evaluate the possible contribution of TNF in MAC-induced
activation of NF-B, U937 cells were preincubated with anti-TNF
Abs followed by stimulation by MAC for 30, 60, and 120 min. As shown in
Figure 6B, preincubation of cells with anti-TNF did not
minimize the NF-B-DNA-binding activity induced by MAC. However,
preincubation with anti-TNF abrogated the TNF-induced
NF-B-DNA-binding activity. These observations suggest that MAC
activated NF-B independently of TNF.
Cellular uptake of MAC is not required for NF-B activation
Whether cellular uptake of MAC is required to activate NF-B was
also investigated. Cytochalasin B is an actin-depolymerizing drug and
inhibits bacterial invasion and phagocytosis (32, 33). We examined the
effect of cytochalasin B on MAC-induced NF-B activation. Our results
showed that inhibition of cellular invasion by pretreatment of U937
cells with cytochalasin B for 30 min followed by incubation with MAC
did not prevent activation of NF-B by the mycobacterium, suggesting
that bacterial invasion is not essential for the activation of NF-B
(Fig. 6C).
MAC-induced NF-B activation is mediated by reactive oxygen
species
Several studies indicate that NF-B activation is mediated
through oxidative stress. Since NF-B activation by a wide variety of
stimuli is inhibited by antioxidants, we tested their role in
inhibition of NF-B induced by MAC. U937 cells were preincubated with
the antioxidant PDTC for different times and then stimulated with MAC
for either 5, 15, or 60 min. As shown in Figure 7, A, B and
C, pretreatment of cells with PDTC inhibited NF-B
activation induced by exposure to MAC for either 5, 15, or 60 min. PDTC
did not inhibit MAC-induced NF-B activation when the two agents were
coincubated (0 time); however, preincubation with PDTC for 1 h
completely blocked the NF-B activation induced by exposure to MAC
for all time points. In some cases preincubation with PDTC for 15 min
reduced the NF-B activation induced by exposure to MAC for 60 min
(Fig. 7C). PDTC by itself did not activate NF-B. We also
examined the effect of other antioxidants such as BHT, BHA, GSH, and
NAC on MAC-induced NF-B activation. Pretreatment of cells for 1
h with BHT, BHA, and GSH also reduced the nuclear NF-B activation
induced by MAC, whereas mannitol and NAC had no effect (Fig. 7D).
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B activation by MAC, we
used human breast adenocarcinoma MCF-7 cells transfected with an
expression vector containing the gene for manganese superoxide
dismutase (MnSOD), an enzyme involved in scavenging of
superoxide radicals. Incubation of control MCF-7 cells (neo)
with MAC for either 15 min (Fig. 8A) or 60 min (Fig. 8B) activated NF-B, but minimal or no activation was
noted in MnSOD-transfected cells. In the same experiment, NF-B
activation by the mycobacterium was also noted in U-937 cells (Fig. 8B). These results strongly suggest that ROI, especially the
superoxide radical, play a role in the MAC-induced signal transduction
pathway leading to NF-B activation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B,
since this bacterium remains one of the most frequent life-threatening
infections in AIDS patients. The transcriptional regulation of HIV is
under the control of NF-B, which binds to two B-binding sequences
present in the HIV long terminal repeat (LTR) to initiate
transcription. Our EMSA data show that infection of cells of both
macrophage and nonmacrophage origin activated NF-B. The response was
by and large similar with high and low virulent strains, but the killed
bacteria produced a delayed response. Activation of NF-B was
persistent and was associated with initial degradation of IB- and
IB-ß. IB- was resynthesized and reached its basal level in
spite of persistent activation of NF-B.
The induction of enhanced NF-B-DNA-binding activity following MAC
infection could be due either to the proteolytic degradation of the
intracytoplasmic inhibitory molecule IB- and IB-ß, or to the
transcriptional activation of the genes encoding the p65/p50 subunits
that are under the transcriptional control of NF-B. From the rapid
induction of NF-B-DNA complex in the nucleus, it is unlikely that
the activation is due to more synthesis of proteins. The dissociation
of NF-B from IB- is the more likely mechanism for the enhanced
NF-B-DNA-binding activity. Indeed, our data on Western blot analyses
of cytoplasmic extracts from MAC-stimulated U937 indicate that
IB- undergoes proteolysis (Figs. 2B and
5B). Persistent activation of NF-B in this study (Fig. 2, A and C) was not, however, associated with
persistent IB- degradation, which may be explained by the fact
that the transcription of IB- is under the control of NF-B.
Resynthesis of cytoplasmic IB- could be the consequence of
increased transcription of the protein under the influence of the
transcription factor B. Persistent activation of NF-B by LPS and
Listeria monocytogenes has also been reported. The initial
rapid but transient activation occurred through the degradation of
IB- while the prersistent activation was mediated through the
degradation of IB-ß (34). The role of lipoteichoic acid (LTA) and
the expression of virulence genes plcA and plcB
encoding two phospholipases have been suggested for the two phases of
activation, respectively, in L. monocytogenes
infection. Examination of IB-ß in our study showed a significant
degradation of this protein during the persistent activation of NF-B
by MAC. These observations suggest the involvement of both IB-
and IB-ß in the signaling pathway.
A number of diverse stimuli, such as cytokines TNF and IL-1, phorbol
esters, bacterial LPS, and certain viruses activate NF-B (21). The
signaling pathways leading to activation of NF-B are different for
these inducers, however, with some common steps. The generation of
abundant ROI is a common signal transduction pathway used by these
agents (35). Measurement of increased production of superoxide or
H2O2 in the stimulated cells and activation of
NF-B by H2O2 support involvement of ROI
(36). The evidence that ROI are signal transducers is the finding that
a variety of chemically distinct antioxidants intercept the activation
of NF-B by the activators investigated so far (37). We speculate
that ROI are involved in the signal transduction pathway by which MAC
activates NF-B. Pretreatment of cells with the antioxidants PDTC,
BHT, BHA, and GSH, but not NAC and mannitol, inhibited the activation
of this transcription factor (Fig. 7), suggesting a potential role for
ROI in MAC-induced activation of NF-B. The reason for these
differential effects of antioxidants is not clear but suggests a
difference in their mechanism of action. Similar results were reported
with a blood protozoan Theileria parva, which also activates
NF-B in T cells (38). Both PDTC and NAC are thiol compounds. PDTC,
however, is a chelator of iron, which may be involved in production of
ROI. This may explain why, in our studies and those reported by others,
PDTC but not NAC inhibited NF-B activation. Since both BHT and BHA
are potent inhibitors of lipid peroxidation, it suggests that this may
also contribute to the mycobacterial activation of NF-B.
To further validate the involvement of ROI in NF-B induction by MAC,
we studied the activation of NF-B in cells transfected with MnSOD, a
mitochondrial enzyme involved in the scavenging of superoxide radicals.
Overexpression of this enzyme has been observed to confer resistance to
TNF-mediated cytotoxicity and activation of NF-B (23, 39). In
contrast to the massive NF-B activation in the neo-transfected MCF-7
cells, no activation of NF-B by high-virulent MAC was evident in
MnSOD-transfected MCF-7 cells (Fig. 8). This result further confirms
the critical role of ROI in the MAC-induced activation of NF-B.
The mycobacterium is known to induce TNF production in macrophages. Due
to the activation of NF-B within 5 min following MAC infection, the
involvement of TNF is unlikely (Figs. 2, A and C,
and 7A). In addition, preteatment of cells with anti-TNF
Ab had no effect on MAC-induced NF-B activation (Fig. 6B). What component of MAC is responsible for activation of
NF-B is unclear. The intracellular or secretory products of the
microbial pathogens Shigella flexneri, Staphylococcus
aureus, Borrelia burgdorferi, and L.monocytogenes do activate NF-B (7, 40, 41). In our studies, the
failure of PB, an inhibitor of LPS, to abrogate the activation of
NF-B by MAC supports the notion that LPS is not involved (Fig. 6A).
Intracellular invasion has been found to be a prerequisite for the
activation of NF-B in Shigella and Listeria
infections (7, 40). Mutant Shigella defective in epithelial
cell invasion did not activate NF-B. Listeriolysin O (LLO), the
outer membrane protein of Listeria, is essential for the
intracellular survival and replication of the pathogens, which are in
turn essential for the expression of listerial phospholipases involved
in the persistent phase of NF-B activation. Host cell invasion was
not, however, an essential prerequisite for MAC activation of NF-B
in our experiments. Pretreatment of U937 cells with cytochalasin B, an
inhibitor of phagocytosis, did not prevent the signal transduction
leading to activation of NF-B by MAC. Furthermore, the activation of
this transcription factor by mycobacteria in the nonphagocytic cell
lines Jurkat and ML-1a support the notion (Figs. 1B and
2C).
The intracellular parasite M. avium complex
induces disseminated disease leading to chronic inflammation and
extensive tissue damage. Interaction of MAC with the mammalian cells in
the present study activated NF-B, which is known to activate
transcription of a variety of inflammatory cytokines, viz., TNF and
IL-1 (42, 43). These cytokines in turn contribute to pathogenesis of
the disease in progress. It is interesting to note that HIV-1 harbors
two NF-B binding sites in its long terminal repeat (LTR)
(44), and the redox regulation of NF-B has been implicated in the
activation of HIV-1. The activation of host cell NF-B by MAC
provides an opportunity for the HIV-1 virus to exploit the
transcription of the viral genome. Antioxidants and NF-B antagonists
could supplement the arsenal of existing therapeutic modalities
in containing pathogens and disease progression.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bharat B. Aggarwal, Cytokine Research Section, Department of Molecular Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 143, Houston, TX 77030. E-mail address:
3 Abbreviations used in this paper: MAC, Mycobacterium avium-intracellulare complex; EMSA, electrophoretic mobility shift assay; ROI, reactive oxygen intermediate; NAC, N-acetylcysteine; BHT, butylated hydroxytoluene; BHA, 3-tert-butyl-4-hydroxyanisole; PDTC, pyrrolidine dithiocarbamate; GSH, glutathione; FS, fibroblast; PB, polymyxin B; MnSOD, manganese superoxide dismutase.
Received for publication March 13, 1998. Accepted for publication June 22, 1998.
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References |
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|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B (RelA/p50) activation induced by lipoteichoic acid and
bacterial phospholipases and mediated by IB- and IBß
degradation. Proc. Natl. Acad.
Sci. USA 94:9394.
B in P388D1
macrophage-like cells. Infect. Immun.
62:2740.
B. Infect. Immun. 64:3845.[Abstract]
B and is a potent inducer of chemokine and adhesion molecule gene expression in endothelial cells and fibroblasts. J. Immunol. 158:3285.[Abstract]
B and inflammatory activation in human endothelial cells. J. Immunol. 157:4584.[Abstract]
B. J. Virol. 69:1480.[Abstract]
B and its inhibitor IB-/MAD-3 in monocytes by Mycobacterium tuberculosis and during human tuberculosis. J. Immunol. 159:4109.[Abstract]
B and activator protein 1 and the induction of inflammatory cytokines. J. Exp. Med. 186:247.B in bovine T lymphocytes. Mol. Cell. Biol. 9:4677.B: a lesson in family values. Cell 80:529.[Medline]
B as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv. Immunol. 65:111.[Medline]
B- requires site-specific ubiquitination. Proc. Natl. Acad. Sci. USA 92:11259.B- ubiquitination in signal-induced activation of NF-B in vivo. J. Biol. Chem. 271:7844.B in the immune system. Annu. Rev. Immunol. 12:141.[Medline]
and/or hyperthermia. Cancer Res. 57:1991.B. J. Biol. Chem. 270:10631.B-like activity in murine bone marrow macrophages. Infect. Immun. 60:2008.B and KBF1 in murine macrophages. Infect. Immun. 63:1960.[Abstract]
B. Infect. Immun. 64:3845.
B and activator protein 1 and the induction of inflammatory cytokines. J. Exp. Med. 186:247.
B-ß regulates the persistent response in a biphasic activation of NF-B. Cell 80:573.[Medline]
B: an oxidative stress-responsive transcription factor of eukaryotic cells. Free Radical Res. Comm. 17:221.
B transcription factor and HIV-1. EMBO J. 10:2247.[Medline]
B activation in intact cells. J. Exp. Med. 175:1181.B regulation in lymphoproliferation caused by Theileria parva infection. Proc. Natl. Acad. Sci. USA 94:12527.B DNA-binding activity. Infect. Immun. 61:4427.B and inflammatory activation in human endothelial cells. J. Immunol. 157:4584.
by monocytes from patients with pulmonary tuberculosis. Infect. Immun. 58:3286.This article has been cited by other articles:
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 V. Mollace, D. Salvemini, D. P. Riley, C. Muscoli, M. Iannone, T. Granato, L. Masuelli, A. Modesti, D. Rotiroti, R. Nistico, et al. The contribution of oxidative stress in apoptosis of human-cultured astroglial cells induced by supernatants of HIV-1-infected macrophages J. Leukoc. Biol., January 1, 2002; 71(1): 65 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yamada, S. Mizuno, M. Reza-Gholizadeh, and I. Sugawara Relative Importance of NF-kappa B p50 in Mycobacterial Infection Infect. Immun., November 1, 2001; 69(11): 7100 - 7105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Reiling, A. Blumenthal, H.-D. Flad, M. Ernst, and S. Ehlers Mycobacteria-Induced TNF-{alpha} and IL-10 Formation by Human Macrophages Is Differentially Regulated at the Level of Mitogen-Activated Protein Kinase Activity J. Immunol., September 15, 2001; 167(6): 3339 - 3345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-Y. Kim and Y. Rikihisa Expression of Interleukin-1beta , Tumor Necrosis Factor Alpha, and Interleukin-6 in Human Peripheral Blood Leukocytes Exposed to Human Granulocytic Ehrlichiosis Agent or Recombinant Major Surface Protein P44 Infect. Immun., June 1, 2000; 68(6): 3394 - 3402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Miettinen, A. Lehtonen, I. Julkunen, and S. Matikainen Lactobacilli and Strepto |
