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Previous Article | Next Article 
Infection and Immunity, November 2001, p. 7100-7105, Vol. 69, No. 11
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.11.7100-7105.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Relative Importance of NF-
B p50 in
Mycobacterial Infection
Hiroyuki
Yamada,
Satoru
Mizuno,
Mohammad
Reza-Gholizadeh, and
Isamu
Sugawara*
Department of Molecular Pathology, The
Research Institute of Tuberculosis, Tokyo 204-0022, Japan
Received 6 June 2001/Returned for modification 12 July
2001/Accepted 27 July 2001
 |
ABSTRACT |
To understand the role of NF-
B in the development of murine
tuberculosis in vivo, NF-B p50 knockout mice were infected with Mycobacterium tuberculosis by placing them in the exposure
chamber of an airborne-infection apparatus. These mice developed
multifocal necrotic pulmonary lesions or lobar pneumonia. Compared with
the levels in wild-type mice, pulmonary inducible nitric oxide
synthase, interleukin-2 (IL-2), gamma interferon, and tumor necrosis
factor alpha mRNA levels were significantly low but expression of IL-10 and transforming growth factor 
mRNAs were within the normal ranges.
The pulmonary IL-6 mRNA expression level was higher. Therefore, NF-B
and its interaction with host cells play an important role in the
pathogenesis of tuberculosis.
| |
INTRODUCTION |
Nuclear factor B (NF-B) is a
ubiquitous dimeric transcription factor whose activity is tightly
regulated by various cytokines and other external stimuli (1,
31). It is retained in the cytoplasm in latent form as a
heterotrimeric complex consisting of p50, p65 subunits, and an
inhibitor, IB. 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 (1, 10).
The nature of the signals that lead to activation of NF-B strongly
implies that NF-B plays a major role in the immune system (for a
review, see reference 10). NF-B plays a role in the activation of immune cells by upregulating the expression of many cytokines essential to the immune responses (1, 10).
Anti-inflammatory drugs inhibit NK-B activation in cultured cells,
indicating that NF-B may be a good target for potential therapy of
chronic inflammatory diseases. NK-B is also involved in
mycobacterial infection, according to research carried out in vitro at
the cellular level (4, 30). Expression of interleukin-2
(IL-2) receptor and activation of IL-6 and IL-8 by Mycobacterium
tuberculosis are mediated by NF-B (30, 33, 35).
Lipoarabinomannan from M. tuberculosis stimulates the
activation of NF-B and KBFI in murine macrophages (3,
4). Moreover, a purified protein derivative induces the
activation of NF-B in monocytes from patients with tuberculosis (31). On the other hand, M. avium-intracellulare complex activates NF-B in different cell
types through reactive oxygen intermediates (11).
However, little is known about the role of NF-B in mycobacterial
infection in vivo. The present study was undertaken to determine the
role of the p50 subunit of NF-B in murine tuberculosis in vivo. We
demonstrate that NF-B p50 plays a major role in mycobacterial infection by augmenting the expression of gamma interferon (IFN-
), IL-2, and tumor necrosis factor alpha (TNF-
).
| |
MATERIALS AND METHODS |
Mice.
Six-week-old C57BL/6 wild-type (WT) mice were
purchased from Japan SLC Co. Ltd. (Shizuoka, Japan). NF-B KO mice of
C57BL/6 origin whose exon 6 of the Nfkb1 gene had been
disrupted by insertion of a vector containing the neo
resistance gene were purchased from Jackson Laboratory (Bar Harbor,
Maine) (22). The mice lacking the p50 subunit of NF-B
showed no developmental abnormalities. Mice lacking the p65 subunit of
NF-B die on day 16 of gestation (10). All mice were
housed in a biosafety level 3 facility and given mouse chow and water
ad libitum after aerosol infection with mycobacteria.
Experimental infections.
The virulent Kurono strain of
M. tuberculosis (ATCC 358121) was grown in Middlebrook 7H9
broth for 2 weeks and then filtered with a sterile acrodisc syringe
filter (Pall Corp., Ann Arbor, Mich.) with a pore size of 5.0 µm.
Aliquots of the filtrate bacterial solution were stored in a freezer at
80°C until use. The mice were infected by being placed into the
exposure chamber of an aerosol generator (Glas-Col, Inc., Terre Haute,
Ind.) in which the nebulizer compartment was filled with 5 ml of a
suspension containing 106 CFU of Kurono tubercle bacilli
under conditions that would introduce about 1,000 bacteria into the
lungs of each animal (26, 34).
CFU assay.
At 1, 3, 5, 7 and 10 weeks after aerosol
infection, groups of mice were anesthetized with pentobarbital sodium,
the abdominal cavities were incised, and exsanguination was carried out
by splenectomy and transection of the left renal artery and vein. The
lungs, spleens, and livers were excised and weighed. The right upper lobes of the lungs and some spleen tissues were weighed separately and
used to evaluate the in vivo growth of M. tuberculosis. The lung and spleen tissue samples were each homogenized with a
mortar and pestle and then placed in test tubes, and 1 ml of sterile saline was added to each sample. After homogenization, 100 µl of the
homogenate was plated in 10-fold serial dilution on 1% Ogawa slant
media. Colonies on the media were counted after a 4-week incubation at
37°C.
RT-PCR.
The right lobes of the lungs and the spleen tissues
were used for reverse transcriptase PCR (RT-PCR) analysis to examine
several cytokine mRNA expression levels in these samples during
M. tuberculosis infection. These tissue samples were
snap-frozen in liquid nitrogen and stored at 85°C until use. RNA
extraction was performed as described previously (25, 26).
Briefly, the frozen tissues were homogenized in a microcentrifuge tube.
Then the homogenates were treated with total RNA isolation reagent,
TRIzol reagent (GIBCO BRL), as specified by the manufacturer. After RNA
isolation, total RNA was reverse transcribed into cDNA with Moloney
murine leukemia virus reverse transcriptase (GIBCO BRL) following
measurement of total RNA concentration, and agarose gel electrophoresis
was performed.
PCR was performed with gene-specific primer sets for -actin,
IFN-, TNF-, IL-1, IL-2, IL-6, IL-10, IL-12p40, transforming growth factor , (TGF-), and inducible nitric oxide synthase (iNOS) genes. For -actin, samples were subjected to 23 cycles of
denaturation (94°C for 1 min), annealing (65°C for 1 min), and
extension (72°C for 2 min); for IFN-, TNF-, IL-1, IL-12p40, and INOS, they were subjected to 30 cycles of denaturation (94°C for
1 min), annealing (65°C for 1 min), and extension (72°C for 2 min);
for IL-2 and IL-6, they were subjected to 40 cycles of denaturation
(94°C for 1 min), annealing (62°C for 1 min), and extension (72°C
for 2 min); for IL-10, they were subjected to 40 cycles of denaturation
(94°C for 1 min) annealing (65°C for 1 min), and extension (72°C
for 2 min); and for TGF- they were subjected to 25 cycles of
denaturation (94°C for 1 min), annealing (60°C for 1 min), and
extension (72°C for 2 min).
The primer sequences and PCR product sizes were as follows: for
-actin, 5'-TGT GAT GGT GGG AAT GGG TCA G-3' (sense) and
5'-TTT GAT GTC ACG CAC GAT TTC C-3' (antisense), 514 bp; for
IFN-, 5'-TAC TGC CAC GGC ACA GTC ATT GAA-3' (sense) and
5'-GCA GCG ACT CCT TTT CCG CTT CCT-3' (antisense), 405 bp;
for TNF-, 5'-ATG AGC ACA GAA AGC ATG ATC-3' (sense) and
5'-TAC AGG CTT GTC ACT CGA ATT-3' (antisense), 276 bp; for
IL-1, 5'-CAG GAT GAG GAC ATG AGC ACC-3' (sense) and
5'-CTC TGC AGA CTC AAA CTC CAC-3' (antisense), 447 bp; for
IL-2, 5'-CTT CAA GCT CCA CTT CAA GCT-3' (sense) and 5'-CCA TCT CCT CAG AAA GTC CAC-3' (antisense), 400 bp; for
IL-6, 5'-CAT CCA GTT GCC TTC TTG GGA-3' (sense) and
3'-CAT TGG GAA ATT GGG GTA GGA AG-3' (antisense), 463 bp;
for IL-10, 5'-CCA GTT TTA CCT GGT AGA AGT GAT-3' (sense) and
5'-TGT CTA GGT CCT GGA GTC CAG CAG-3' (antisense), 324 bp;
for IL-12p40, 5'-ATC TCC TGG TTT GCC ATC GTT TTG-3' (sense)
and 5'-TCC CTT TGG TCC AGT GTG ACC TTC-3' (antisense), 527 bp; for TGF-, 5'-CGG GGC GAC CTG GGC ACC ATC CAT GAC-3'
(sense) and 5'-CTG CTC CAC CTT GGG CTT GCG ACC CAC-3'
(antisense), 371 bp; and for iNOS, 5'-TGG GAA TGG AGA CTG
TCC CAG-3' (sense) and 5'-GGG ATC TGA ATG TGA TGT TTG-3'
(antisense), 306 bp.
Amplification was carried out with a thermal cycler (model 480, Perkin-Elmer Cetus). A 10-µl volume of each PCR product was used for
electrophoresis in a 4% agarose-NuSieve GTG (1:3) gel and visualized
using ethidium bromide staining.
Light and electron microscopy.
For light microscopy, the
left lobes of the lungs were excised and fixed with 20%
formalin-buffered methanol solution, Mildform 20NM (containing 8%
formaldehyde and 20% methanol) (Wako Pure Chemical Co., Osaka, Japan),
dehydrated with a graded ethanol series, treated with xylene, and
embedded in paraffin. Sections 5 µm thick were cut from each paraffin
block and stained with either hematoxylin and eosin or Ziehl-Neelsen
stain for acid-fast bacilli.
For electron microscopy, the right upper lobe of the lung was fixed
with 2.5% glutaraldehyde in 0.1 M phosphate buffer (pH 7.4)
(PB) at 4°C overnight, washed three times with cold PB,
postfixed with 1% osmium tetroxide in PB at 4°C for 1 h,
dehydrated with a graded acetone series, and finally embedded with
Spurr's low-viscosity resin. Ultrathin sections were obtained using a
Reichert Ultracut microtome and stained with uranyl acetate and Sato's
lead solution. The stained ultrathin sections were examined using a
1200EX electron microscope (JEOL, Tokyo, Japan).
Statistical methods.
The values were compared by Student's
t test. For all statistical analyses, differences at
P < 0.01 were considered significant.
| |
RESULTS |
Mycobacterial burden in the lungs and spleens of NF-B KO
mice.
NF-B is a transcription factor that plays an important
role in the expression of many immunological mediators, including cytokines, their receptors, and components of their signal
transductions. To clarify the role of NF-B in experimental
tuberculosis, C57BL/6 WT mice and mice lacking the p50 subunit of
NF-B (Nfkb1 gene disrupted) (NF-B KO mice) were
infected with the virulent Kurono strain of M. tuberculosis
using an aerosol infection apparatus (26, 28). C57BL/6 WT
mice survived the entire 12-week experimental period, but NF-B KO
mice began to succumb to the disease at 6 weeks after infection, and
all mice had died by 10 weeks after infection (Fig.
1). The numbers of recovered tubercle
bacilli from the lungs and spleen tissue of infected animals after
aerosol infection are shown as CFU in Fig.
2. At 1 week after infection, tubercle
bacilli were recovered only from the lung tissues of C57BL/6 WT mice.
However, by 3 weeks after infection, the mycobacterial load in the
organs had increased in NF-B KO mice. Both the WT and KO groups
showed similar patterns of bacterial growth in the lungs and spleen.
Surprisingly, at 5 weeks after infection, NF-B KO mice contained
2,500-fold more tubercle bacilli in the lungs and 1,000-fold more
tubercle bacilli in the spleen tissues than the WT mice did.
Furthermore, this high bacterial load continued up to 10 weeks after
infection, although a slight decrease in CFU was observed at 7 weeks.
On the other hand, in WT mice, the CFU in both the lung and spleen
tissues reached a peak at 3 weeks after infection and there was no
major change in the number of CFU after 5 weeks.
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FIG. 1.
Survival curves of mice infected with M. tuberculosis Kurono strain. The data presented are from two
separate experiments with 10 mice in each group.
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FIG. 2.
CFU in lung and spleen tissues of NF-B KO and WT mice
(10 mice each) exposed to 106 CFU of M. tuberculosis Kurono strain by the airborne route. At the indicated
days after infection, three mice from each group were sacrificed and
homogenates of lung and spleen tissues were plated. Error bars indicate
standard deviations of the means.
|
|
Light and electron microscopic observation of infected lungs.
In accordance with the CFU changes, histopathological findings obtained
from C57BL/6 WT and NF-B KO mice showed similar changes at 3 weeks after infection, but at 5 weeks, NF-B
KO mice showed extremely severe pathological changes, especially in the
infected lung tissues (Fig. 3). Pulmonary
histopathology in the NF-B KO mice at 5 weeks after infection
revealed findings characterictic of lobar pneumonia, which was induced
by the tubercle bacilli. In the pulmonary lesions, there was severe
inflammation in which numerous macrophages ingesting many mycobacteria
filled up the alveolar spaces, and some necrotic changes were noted,
especially in the middle lobes. These severe pathological changes were
not observed in the WT mice.
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FIG. 3.
Histologic examination of lung tissues. Mice were
killed 5 weeks after airborne infection with M. tuberculosis
Kurono strain, and formalin-fixed sections were stained with
hematoxylin and eosin (A and C) or Ziehl-Neelsen stain for acid-fast
bacilli (B). (A) Pulmonary tissue from an NF-B KO mouse infected
with Kurono strain. Almost necrotic lesions with numerous neutrophils
and epithelioid macrophages (arrow) are shown. Magnification, ×315.
(B) Pulmonary tissue from an NF-B KO mouse infected with Kurono
strain. Many acid-fast bacilli are recognized in the necrotic lesion by
Ziehl-Neelsen staining. Magnification,×540. (C) Pulmonary tissue from
a WT mouse infected with Kurono strain. A discrete granulomatous lesion
is recognized. Magnification, ×135.
|
|
Electron microscopy demonstrated that alveolar macrophages in NF-B
KO mice phagocytosed more tubercle bacilli and that the engulfed
tubercle bacilli were located in phagosomes and appeared to escape the
host cell killing mechanism. No escape by M. tuberculosis from phagosomes to the cytoplasm was observed. Tubercle bacilli in the
phagosomes of macrophages were relatively long and contained many large
vacuole-like structures (Fig. 4).
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FIG. 4.
Electron micrographs of lung tissue from WT (a) and
NF-B KO (b) mice infected with Kurono strain, obtained 5 weeks after
airborne infection. (a) Phagolysosomal fusion (arrows) incorporating
many tubercle bacilli is prominent. Magnification, ×5,000. (b) Many
phagosomes (arrows) ingest tubercle bacilli. Magnification, ×5,000.
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|
RT-PCR analysis.
Because the mycobacterial CFU assay and
histopathological examination indicated that NF-B KO mice were much
more susceptible to M. tuberculosis infection than WT mice
were, we performed RT-PCR to compare the expression levels of major
cytokine mRNAs in the lung and spleen tissues of NF-B KO mice with
those in tissues of WT mice. Figure 5
shows the results of RT-PCR in the infected lung tissues at 1, 3, 5, and 7 weeks after infection. Expression of IFN-, TNF-, IL-2, and
iNOS mRNAs in NF-B KO mice was significantly lower than that in WT
mice until 3 weeks after infection. In particular, IL-2 mRNA expression
was very low at 1 and 3 weeks. From 5 weeks after infection onward, the
expression levels of these cytokine mRNAs became comparable to those in
WT mice. NK-B KO mice exhibited reduced IL-1 mRNA expression
compared to that of WT mice at 1 and 3 weeks after infection. Except at
5 weeks after infection, NF-B KO mice exhibited reduced IL-12 p40
mRNA expression compared to that of WT mice. On the other hand,
expression of IL-10 and TGF- mRNAs in NF-B KO mice was similar to
that in WT mice, and there was no significant difference in expression
intensity between the two groups (P < 0.01). The level
of expression of IL-6 mRNA in the two groups was reversed, because the
amplified band of the RT-PCR products in NF-B KO mice was more
intense than that of WT mice for the entire experimental period.
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FIG. 5.
In vivo expression of various cytokines and iNOS mRNA in
Kurono strain-infected mice by RT-PCR. The lung tissues of NF-B KO
and WT mice were removed 1, 3, 5, and 7 weeks after airborne infection.
-Actin gene primer sets were used as an internal control. IFN-,
IL-2, IL-1, IL-12, iNOS, and TNF- mRNA expression is low in
NF-B KO mice. W, wild type; K, knockout; M, size marker.
|
|
| |
DISCUSSION |
We investigated the role of NF-B in mycobacterial infection in
vivo. In the absence of NF-B activation, the NF-B KO mice were
highly susceptible to M. tuberculosis infection. Under these conditions, Th1 cytokine IL-2 and IFN- and TNF- secretion
levels were significantly low. Although it is reported that NF-B is required for transcription of Th1 type cytokines, the equivalent mRNA
expression levels between WT and NF-B p50 KO are recognized at 5 and
7 weeks after infection (10). There may be another mechanism of transcription (for example, activation of AP-1). It has
been reported that IFN- and TNF- play a major role in defense
against mycobacterial infection (2, 5, 7, 8, 17, 25). It
is also known that IL-2 augments NK cell activity and stimulates
macrophages (19). NF-B stimulates the production of
various cytokines (reviewed in reference 10). Furthermore, some of these cytokines activate NF-B themselves, thus initiating an
autoregulatory feedback loop. In NF-B KO mice, NF-B cannot induce
the expression of IL-2, IFN- or TNF- mRNA. This is why NF-B KO
mice cannot survive mycobacterial infection for very long. The NF-B
p50 KO mice used in our experiments are known to have B-cell
dysfunction, although they show no developmental abnormalities
(22). B cells do not proliferate in response to bacterial
lipopolysaccharide and are defective in basal and specific antibody
production in these mice. It is thought that humoral immunity
abonormality has little effect on the development of murine
tuberculosis because B cells are not involved in the mycobacterial inflammatory process (13).
iNOS mRNA expression was also depressed in NF-B p50 KO mice. As
evaluated by electron microscopy, tubercle bacilli were proliferating in macrophage phagosomes. In fact, the NO activity of alveolar macrophages from NF-B KO mice was significantly lower than
that from wild-type mice as assessed by an NO assay with Griess
agent (reference 12 and data not shown). Low NO activity
is due to reduced iNOS mRNA expression in the absence of NF-B p50.
Although IL-1 activates NF-B, the level of expression of IL-1
mRNA was within the normal range. Two IL-1-mediated signaling pathways
result in the activation of NF-B and activating protein (AP-1) to
express inflammatory cytokines (6, 19, 32). In NF-B KO
mice, AP-1 is induced to express IL-1 although NF-B is not induced
at all; this explains the normal expression of IL-1 mRNA. However,
AP-1 is not involved in the TNF--mediated signaling event, which
explains the low TNF- mRNA expression in the infected NF-B KO
mice. Although it is expected that IL-6 mRNA expression will be
depressed in NF-B KO mice, IL-6 mRNA expression was higher than that
is WT mice. Our NK-B KO mouse strain is a p50 KO strain, and p65
functions in these mice. Mice lacking this p65 gene die on day 16 of
gestation (10). IL-6 is produced by macrophages and Th2.
It is known that IL-10 inhibits IL-6 production and expression of IL-6
mRNA posttranscriptionally in monocytic cell lines (27).
In our present study, the IL-10 mRNA expression level is low, and this
explains the high expression of IL-6 mRNA. IL-6 mRNA expression may be
activated in the NF-B p50 KO mice. Further study is required to
explain the high IL-6 mRNA expression in the NK-B p50 KO mice.
IL-10 and IL-12 mRNA expression levels are low in the NK-B p50 KO
mice. It is known that IFN- augments IL-12 production by macrophages
(18). Low IFN- production may explain the low IL-12
level in our NK-B KO mice. Low IL-12 mRNA expression may be
associated with lack of p50 NF-B activation (23). It is remain unclear whether low IL-10 mRNA expression is associated with low
IL-12 mRNA expression. Similar to the report that human monocyte-derived macrophages infected with M. smegmatis
19-kDa lipoprotein result in reduced production of IL-12 and IL-10,
such an event may occur in M. tuberculosis infection
(21).
It is important to examine the roles of various transcription factors
in inflammatory processes because they control major cytokine
expression. We have previously reported that NF-IL6 KO mice developed
lethal multifocal necrotic mycobacterial lesions in the lungs, spleen,
and liver (26). Since NF-IL6 controls granulocyte
colony-stimulating factor expression (28), we stressed the
relative importance of neutrophils stimulated by G-CSF in the early
phase of mycobacterial infection. It has also been reported that
activation of IL-6 by M. tuberculosis or lipopolysaccharide is mediated by NF-IL6 and NF-B (35). Both NF-IL6 and
NF-B are required for efficient expression of IL-6. In the present study, the importance of NF-B in the development of murine
tuberculosis was demonstrated. The importance of NF-B in infection
by other intracellular pathogens and parasites, such as Listeria
monocytogenes, M. avium-intracellulare, Treponema pallidum, Rickettsia
rickettsii, Theileria parva, and Salmonella enterica
seravor Typhimurium, has also been reported (9, 11, 14, 15,
20). Intracellular invasion was found to be a prerequisite for
the activation of NF-B.
In summary, NF-B activation is a consequence of the interaction of
host cells with mycobacterium, and this interaction may play a pivotal
role in the pathogenesis of tuberculosis.
| |
ACKNOWLEDGMENT |
This study was supported in part by an International
Collaborative Study Grant to the chief investigator, Isamu Sugawara, from the Ministry of Health, Labor and Welfare, Japan.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Molecular Pathology, The Research Institute of Tuberculosis, 3-1-24 Matsuyama, Kiyose, Tokyo 204-0022, Japan. Phone: 81 424 93 5075. Fax:
81 424 92 4600. E-mail: sugawara{at}jata.or.jp.
Editor:
J. T. Barbieri
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Infection and Immunity, November 2001, p. 7100-7105, Vol. 69, No. 11
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.11.7100-7105.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
